pH in Cancer & Tumor Acidification: A Top Treatment Strategy


pH and Cancer is an intensively discussed subject both in the alternative treatment arena and fortunately more and more in the scientific arena. In terms of treatments, when we speak about pH in cancer I am thinking of treatments involving e.g. the well known Sodium Bicarbonate, Cesium Chloride, Germanium, etc. I am also thinking of diets such as the alkaline diet. However, although all of these have their own relevance, these are not the approaches that I intend to discuss in this article. Instead, I will discuss a treatment approach that for some may be new but one that has been already used by some of the most open minded oncologist of this world to treat cancer patients while achieving great results. Here is a nice example of that: Ref.

According to the reference above, the Spanish Dr. Salvador Harguindey is maybe the first and one of the few clinical oncologist worldwide who experimented this approach in cancer patients. He is also one of the leaders of the Association for Proton Cancer Research and Treatment, a fast growing association of scientists working on solving the cancer challenge via a pH perspective.

I strongly believe that manipulating pH is a major way to fight cancer.

Note that manipulating pH is not only relevant as a stand alone anti cancer strategy but it can also be a way to reduce or eliminate some of the main resistance mechanism of tumors to chemotheraphy (Ref.1 Ref2, Ref3, Ref4, Ref5, Ref6).

Update 02-April-2017: Please note that pH manipulation may affect the effectiveness of chemo both ways depending on the type of chemo and the chosen pH strategy. This is further discussed in the “Mechanism” section.


Before going into the discussion of the concept of this relatively new treatment strategy, I would like to clarify a bit the framework. I will not go to deep into the scientific details, but just enough so that we understand the concept.

First, it is important to realize that when speaking about pH many think that the pH in cancer is low. That is true but only partially. That is because indeed the pH is low around the tumors but not inside the tumor cells. Instead, the intra cellular pH in the cancer cells is usually higher compared to the normal cells. This is a bit “strange” given that cancer cells are producing a lot of acidity (i.e. protons) while generating their energy.

Indeed, it is well known that cancer cells are using a lot of glucose to produce energy and other elements required for their existence. Due to the fact that the engine of the cell (mitochondria) works slower than usually or doesn’t work at all in some cases, cancer cells uses another mechanism to produce energy and the other components. This alternative mechanism is called glycolisis or better known as fermentation. However, fermentation is a less effective mechanism compared to the usual cell respiration and as a result it requires more glucose to produce the same amount of energy. This intensive use of glucose leads not only to energy production but as a side effect, it produces a lot of protons (i.e. acidity).

Since the cancer cells like to have high pH (i.e. low acidity) inside (i.e. in the cytosol), they developed a way to push all that outside the cell. In order to push the acidity out, the cancer cells developed much more acidity transporters compared to the normal cells. Some of the most relevant and well known transporters are:

  1. Sodium/Hydrogen exchange, an antiporter which enables the cells to exchange protons for Sodium, i.e. Sodium in and acidity out – maybe the most relevant for balancing the pH – well known to be over expressed in many cancers. We may even argue here that as a cancer patient eating a lot of salt will add enough sodium in our body to keep this pump running well, which is not something we want.
  2. Carbonic anhydrase 9 (CAIX) this is an enzyme that helps extracellular CO2 to become HCO3 (bicarbonate ion). This bicarbonate ion than goes into the cell via the bicarbonate transporter and combines (via CAII enzyme) with a proton resulting CO2 and H20 which are finally pushed out through the cell membrane. This is a way for the cancer cell to annihilate intracellular protons and thus mantain an increased intracellular pH – well known to be over expressed in many cancers (Ref.1, Ref.2, Ref.3)
  3. Vacuolar-type (V-type) H(+)-ATPases – this is one of the three types of ATP driven H+ pumps identified that pump protons across the plasma membrane (Ref.)
  4. Monocarboxylate 4 (MCT4) – a transporter that exports lactate, another result of glycolisis, and proton as lactic acid into the tumor environment – well known to be over expressed in many cancers (Ref.)

Other “knobs”” to turn and modulate pH are related to

  • ATP synthase (Ref)
  • lysosomes (Ref)
  • Na/K exchange (Ref)
  • H/K ATPases (Ref)
  • and even with the thyroid hormones which seems to modulate Na/H exchange (Ref)
  • the bicarbonate transporter family (BCT) (Ref.)
  • Histone deacetylases, HDAC (Ref.)
  • Carbonic anhydrase 12 (CAXII) (Ref.1, Ref.2)
  • acidification of the tumor can also be achieved by reduction in blood flow to tumors relative to normal tissues (Ref.)

Interestingly, drugs that modulate the above “knobs” are all known to have strong anticancer effects via various mechanisms other than pH modulation. However, only recently it has been identified that what they all have in common is their influence on pH.

Here are some links to pictures explaining intracellular processes:

Therefore, using mechanism such as those mentioned above, cancer cells are pushing the acidity from inside out so that a balanced internal pH is maintained. As a result, tumors have a lower extracellular pH (6.7–7.1) than normal tissues (7.4). (Ref.) Beside the fact that the intracellular pH stays as required for the normal function of cancer cells,  this acidity export additionally helps the tumors with the following:

  • lactic acid serves as fuel for other cancer cells that have the capability to import lactate and use it to produce energy via normal respiration
  • acidity promotes the metastasis process
  • acidity inhibits the immune system (Ref.) by e.g. inhibiting the MCT1 in T cells (Ref1, Ref2) or affecting macrophages (Ref.)
  • acidity reduces or cancels the effect of chemotheraphies that are week basis
  • and much more ….

It has been recently shown that any drug that can increase intracellular acidity will lead to the reduction and possibly inhibition of Wnt signaling (Ref.), a mechanism that is highly relevant in cancer (Ref.). In this study, drugs used to increase the intracellular acidity were e.g. Metformin, Papaverine, also known as mitochondria inhibitors (Ref.).

Update 26 August 2019: A paper indicating another mechanism used by the cancer cells to regulate pH inside the cells
The authors suggest that cancer cells use glutaminolysis pathway to produce ammonia, that balances the excessive acidification associated with tumor cell proliferation. This mechanism is similar to that in renal tubule epithelial cells, where ammonia produced from glutaminolysis is critical to form ammonium ions that are further metabolized to urea and excreted.
Therefore inhibiting glutaminolysis would further help. Here I discussed a few of them but Metformin and EGCG extract fro green tea (found as a supplement online) may help.

Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment (Ref.)

pH and Chemo

Update 02-April-2017: pH manipulation may affect the effectiveness of chemo both ways depending on the type of chemo and the chosen pH strategy:

If the chemo used is a weak basis (such as Gemcitabine, Doxorubicin, Daunorubicin, Mitoxantrone, Epirubicin, Idarubicin, Valrubicin, Bleomycin, Vinca alkaloids such as Vinorelbine, etc.) (Ref.1, Ref.2) low pH around the tumors may reduce or inhibit the effect of chemotherapy as the chemo will be “deactivated” before accessing the tumor (Ref.). Therefore, when using such chemos, using strategies to increase the pH (i.e. lower acidity) prior to chemo can increase the effectiveness of chemos (Ref.1, Ref.2, Ref.3)
Epirubicin, for example also a weak base with a pKa of 8.1 and has been shown to exhibits increased efficacy against cancer in alkaline environment. (Ref.)

Note that the weak basis chemotheraphies such as Doxorubicin have been shown to undergo ion trapping and sequestration into acidic vesicles within the cytoplasm.  This process has been associated with drug resistance (Ref. and here is available as a pdf). In simple words, if the weak base type of chemo succeeds to pass through the acidic environment and enter the cancer cells, chemo may be attracted like a magnet in to some storage rooms within the cells and made inactive (Ref.).These storage rooms (lysosomes) attract chemo because they are acidic. In order to lower their acidity and stop them trapping chemo, we can consider the use of drugs known to lower lysosome acidity. One such drug is Omeprazole (Ref.).

Here is a nice clinical study on animals showing how indeed chemo such as Mitoxantrone, a weak basis, can lead to high anti cancer effectiveness when supported by a strategy focused on increasing pH

On the other hand, if the chemo is weak acid (such as Cyclophosphamide, 5-Flourouracil*, Chlorambucil, Cisplatin**, Carboplatin, Mitomycin C, Melphalan, etc.) (Ref.1, Ref.2), low extracellular pH (i.e. higher acidity) will leads to enhanced absorption and cytotoxicity (Ref.1, Ref.2, Ref.3). Same seems to apply for Capecitabine (Xeloda) (Ref.) which is a weak acid (Ref.). Therefore for these or similar chemos, proton pump inhibitors are best avoided.

If the chemo use is neutral, such as it is the case of Taxol, the extracellular acidity will not affect chemo effectiveness (Ref.).

*Interestingly, 5FU is a weak basis (Ref.) but its accumulation inside cancer cells increase when extracellular pH is lower However, on the other hand there are studies showing that Omeprazole, a drug inducing higher extracelular pH can also help 5FU which is puzzling to me and needs to be further clarified
An article discussing this aspect is here

**Cisplatin is a weak acid (Ref.1), however it seems that in some cases it is also potentiated by  a strategy focused on increasing extracellular pH (Ref.). Yet, it is not very clear to me if the Platins are on the acid or base side according to the following reference (Ref.) but also various papers some claiming it is base (Ref.) and others acid (Ref.).
This article suggests Cisplatin is an acid:
Update August 2019: This article, nicely explains that there is scientific evidence indicating Cisplatin may be a proton pump inhibitor itself acting as a Sodium/Hydrogen exchange inhibitor : “Thus, NHE-1 inhibition by cisplatin can play an important role in its antineoplastic effect.” (Ref.). This explains why combining Cisplatin with other proton pump inhibitors will increase anti-cancer effectiveness observed in other experiments.

Extracellular pH has no effect on paclitaxel cytotoxicity (Ref.)

Treatment Strategies:

So what we have seen so far is that:

  • cancer cells like to have an internal pH relatively high, higher than that inside normal cells
  • cancer cells are intensively producing acidity during the energy production process, and this needs to be pushed out of the cancer cell

Based on these specific characteristics of cancer cells we can imagine the following treatment strategies that can work against cancer cells:

  1. Intracellular Alkalinization: increase further the intracellular pH of cancer cells (using e.g. Cesium Chloride, Germanium) to a level that is not sustainable for the cancer cells
  2. Intracellular Acidification: decrease the intracellular pH of cancer cells to a level that is not sustainable for the cancer cells (additionally this will lead to a increase of extracellular pH, or extracellular alkalinization)
  3. Extracellular Alkalinization: increase of the extracellular pH (e.g. using sodium bicarbonate, alkaline diet, etc.) to create an environment unsuitable for cancer growth and activate the immune system. (Ref.)

exhaustOne of the most powerful technique in my opinion is to focus on further decreasing the intracellular pH, i.e. internal acidification. The concept is very simple and it may be easier to achieve compared to the strategy to further increasing the internal pH (alkalinization), since the cancer cells are continuously producing acidity. Intracellular acidification can be achieved by inhibiting some or all of the major acidity transporters discussed above. Actually this strategy can be seen as pushing a banana or a potato into the exhaust pipe of a car so that the smoke can not go out. Since some cancers may use multiple “exhaust pipes” all these pipes may need to be inhibited for the best effect while in others such as melanoma one “pipe” only inhibition (MCTs inhibition only) may be enough (Ref.). On the same line, in a case of ovarian cancer, Sodium/Hydrogen inhibition was enough (Ref.)

This strategy not only puts pressure on the cancer cells due to the intracellular acidification but also leads to immune activation (Ref.), increase chemo- and radio- therapy effectiveness and reduced chance of metastasis. Here is a good PhD thesis explaining in more details how the MCT4 inhibition helps the activity of the immune system: Targeting MCT4 for treatment of advanced prostate cancers

Intracellular acidification and its application:

Here are some elements that can be used alone or in combination with a focus on reducing or inhibiting the major acidity exporters and the related doses as indicated in various publications:

  • Sodium/Hydrogen exchange inhibitors:
    • Amiloride, Ellagic Acid (Ref.)
      Amiloride 5-10mg 2x/day (Ref.)
    • DHA and thus Omega 3 also inhibits this exchanger  (Ref.)
    • Cimetidine (Ref.)
    • Ang II also activates NHE-1 in various tissues. Ang II type 1–receptor blockers such as Olmesartan can inhibit activation of NHE-1 by the Ang II (Ref.)
    • Propranolol (Ref.)
  • Carbonic anhydrase 9 (CAIX) inhibitors:
    • Acetazolamide 250mg/day
    • Note: Statins also inhibit CAIX (Ref.)
    • Topiramate (anti-epileptic drug) (Ref.)
    • Sulthiame (Ref.)
  • Vacuolar-type (V-type) H(+)-ATPases inhibitors:
    • Omeprazole or Pantoprazole or Lansoprazole. Lansoprazole may be more effective (Ref.) Even 3BP seems to be an inhibitor here (Ref.). DCA may also act on the same line (Ref.)
      Omeprazole is given at a dose of about 40 to 80mg/day or higher
  • Monocarboxylates (MCT):
    • Statins such as Simvastatin, Quercetin (Ref.), Phloretin/Phlorizin, Ibuprofen, Aspirin, Syrosingopine (Ref.), Acriflavine (Ref.), Cinnamic acid (Ref.) etc.
      Quercetin is used 5g 2x/day (total 10g/day) or 3g 3x/day (total 9g/day)
    • Interesting enough, this study (Ref.) shows that DMSO is also an intracellular acidifier with anticancer properties and is suggested to be due to the impact on MCTs.
    • Update Oct 2019: Here is a recent study discussing the expression of MCTs in various cancers, and inhibitors such as those discussed above (Ref.)
    • Lonidamine (Ref.)

Acidification of the tumor can also be achieved by reduction in blood flow to tumors relative to normal tissues (Ref.) The vasodilator hydralazine is thought to act on the arteriolar smooth muscle, and since a large proportion of tumor blood vessels lack smooth muscle, they do not respond to the drug. As a result it has been argued that this leads to a redistribution of cardiac output away from the tumor, thus selectively reducing tumor blood flow, with a consequent reduction in tumor pH. Indeed it was shown a 0.4 pH unit drop in tumor pHi 20–40 min following intravenous administration of hydralazine to RIF-1 tumor-bearing mice (Ref.1, Ref.2) Note, I would not use hydralazine in combination with chemo as it would lead to lower blood flow to the tumor and thus less drug available at the tumor site.

Extracellular Alkalinization:

In contrast to many statements from various persons arguing that oral Bicarbonate can not induce a change of tumor extracellular pH since the blood pH is constantly adjusted and maintained to a stable value by various mechanisms in the human body, it has been actually shown that oral Bicarbonate can indeed change the pH at the tumor site and can even reverse the pH gradient (Ref.). The extracellular pH becomes especially important in the therapy of bladder, renal and esophago-gastric cancers where extreme acidity of the extracellular milieu is the norm (Ref.).  Raising intratumoral (extracellular) pH through oral buffers therapy can improve responses to immunotherapy (Ref.) and reduce metastasis formation (Ref.).

Bicarbonate, has also been shown to add value to transarterial chemoembolization (TACE). A pilot clinical investigation in hepatocarcinoma patients was performed, where patients were treated with TACE with or without bicarbonate local infusion into tumor. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may indeed add survival benefit (Ref.1, Ref.2).


Note that Amiloride usage may lead to increase of potassium in the blood which can be dangerous. So I would make sure a doctor is following the patient with blood tests every two weeks.

Watching calcium levels is prudent when taking a PPIs such as Omeprazole.


Amiloride, Acetazolamide, Statins (drugs on prescription) are available at online pharmacies such as

Omeprazole is over the counter drug or can also be probably found at the pharmacies above and on eBay.

Quercetin is a supplement available online.

Clinics treating patients focused on the low pH strategy:

Application on humans:

Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer.

BACKGROUND: Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).
METHODS: Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m(2) followed by cisplatin 75 mg/m(2) on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.
RESULTS: Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (67.7 % vs. 46.9 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045) [corrected]. Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.
CONCLUSIONS: The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.

Long term remission of metastatic ovarian cancer after chronic treatment with the Na+ -H + antiport inhibitor amiloride


Chloroquine: Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

Local Hyperthermia (Ref1, Ref2, Ref3, Ref4)


Cimetidine: “It is generally preferred to pre-treat the tumour patient with another antacid, such as calcium carbonate, or antacid drug, such as an H2-receptor antagonist, for example ranitidine or cimetidine, in order to inhibit acid secretion in the stomach, thereby enhancing the concentration of PPI able to reach the tumour site, and minimising the concentration remaining in the stomach. Thus, treatment with an antacid is effective to increase the delivery of PPI to the acidic tumour, as the number of only acidic sites in the body is substantially reduced or, at least, the most significant site is temporarily neutralised, or ameliorated.”


Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs – an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research

In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or “proton reversal”). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.

Long term remission of metastatic ovarian cancer after chronic treatment with the Na+ -H + antiport inhibitor amiloride

Proton pump inhibitors for the treatment of cancer in companion animals.

The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

Evidence-based support for the use of proton pump inhibitors in cancer therapy.

‘We can only cure what we can understand first’, said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don’t know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg’s discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale.

Tumor Acidity as Evolutionary Spite

Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment.

A rationale for the use of proton pump inhibitors as antineoplastic agents.

It is becoming increasingly acknowledged that tumorigenesis is not simply characterized by the accumulation of rapidly proliferating, genetically mutated cells. Microenvironmental biophysical factors like hypoxia and acidity dramatically condition cancer cells and act as selective forces for malignant cells, adapting through metabolic reprogramming towards aerobic glycolysis. Avoiding intracellular accumulation of lactic acid and protons, otherwise detrimental to cell survival is crucial for malignant cells to maintain cellular pH homeostasis. As a consequence of the upregulated expression and/or function of several pH-regulating systems, cancer cells display an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe). Among the pH-regulating proteins, proton pumps play an important role in both drug-resistance and metastatic spread, thus representing a suitable therapeutic target. Proton pump inhibitors (PPI) have been reported as cytotoxic drugs active against several human tumor cells and preclinical data have prompted the investigation of PPI as anticancer agents in humans. This review will update the current knowledge on the antitumor activities of PPI and their potential applications.

Manipulating tumor acidification as a cancer treatment strategy.

Manipulation of the extracellular and/or intracellular pH of tumors may have considerable potential in cancer therapy. The extracellular space of most tumors is mildly acidic, owing to exuberant production of lactic acid. Aerobic glycolysis – attributable largely to chronic activation of hypoxia-inducible factor-1 (HIF-1) – as well as tumor hypoxia, are chiefly responsible for this phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But there is growing evidence that extracellular acidity per se boosts the invasiveness and metastatic capacity of cancer cells; moreover, this acidity renders cancer cells relatively resistant to the high proportion of chemotherapeutic drugs that are mildly basic, and may impede immune rejection of tumors. Thus, practical strategies for raising the extracellular pH of tumors may have therapeutic utility. In rodents, oral administration of sodium bicarbonate can raise the extracellular pH of tumors, an effect associated with inhibition of metastasis and improved responsiveness to certain cytotoxic agents; clinical application of this strategy appears feasible. As an alternative approach, drugs that inhibit proton pumps in cancer cells may alleviate extracellular tumor acidity while lowering the intracellular pH of cancer cells; reduction of intracellular pH slows proliferation and promotes apoptosis in various cancer cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have markedly impeded tumor growth and prolonged survival in nude mice implanted with a human melanoma. Finally, it may prove feasible to exploit the aerobic glycolysis of cancers in hyperacidification therapies; intense intracellular acidification of cancer cells achieved by induced hyperglycemia, concurrent administration of proton pump inhibitor drugs, and possibly dinitrophenol, may have the potential to kill cancer cells directly, or to potentiate their responsiveness to adjunctive measures. A similar strategy, but without proton pump inhibition, could be employed to maximize extracellular tumor acidity, enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive nanoparticles.

Influence of Tumor pH on Therapeutic Response

The intratumor microenvironment is intrinsically acidic due mainly to accumulation of lactic acid as a result of increased aerobic and anaerobic glycolysis by the tumor cells. In general, the extracellular pH (pHe) in human tumors is below 7.0, whereas the intracellular pH (pHi) is maintained at neutral range, i.e., >7.0, by powerful pHi control mechanisms. The low pHe and the significant gradients between pHe and pHi affect markedly the response of tumors to various treatments such as chemotherapy, radiotherapy and hyperthermia. For instance, the acidic pHe increases the cellular uptake of weakly acidic drugs such as cyclophosphamide and cisplatin and thus increases the effect of the drugs, whereas the acidic pHe retards the uptake of weakly basic drug such as doxorubicin and vinblastine, thereby reducing the effect of the drugs. The radiationinduced apoptosis is suppressed by an acidic environment, whereas the hyperthermiainduced cell death is potentiated by an acidic environment. Better understanding of the control mechanisms of pHe and pHi in tumors may lead to device effective treatment strategy of human tumors.

Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function

Vacuolar H+-ATPase (V-ATPase) is a highly evolutionarily conserved enzyme, which is distributed within the plasma membranes and the membranes of some organelles such as endosome, lysosome and secretory vesicle. The mayor function of V-ATPase is to pump protons across the cell membrane to extracellular milieu or across the organelle membrane to intracellular compartments. V-ATPases located in cell surface act as important proton transporters that regulate the cytosolic pH to ~7.0 which is essential for most physiological processes, whereas V-ATPases within intracellular membrane are involved in cellular processes as receptor-mediated endocytosis, membrane trafficking, protein processing or degradation, and nutrients uptake (Nishi et al., 2002; Forgac et al., 2007; Toei et al., 2010; Cruciat et al., 2010). Malfunctioned V-ATPase is closely related to several diseases including tumor. More and more evidences indicate that V-ATPase is an enhancer for carcinogenesis and cancer progression, such as malignant transformation, growth and proliferation, invasion and metastasis, acquirement of multi-drug resistance, etc., which strongly supports that V-ATPase should be an effective target of anticancer strategy (Fais et al., 2007).

Hypoxia signalling in cancer and approaches to enforce tumour regression

Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.

How cancer metabolism is tuned for proliferation and vulnerable to disruption

Cancer metabolism has received a substantial amount of interest over the past decade. The advances in analytical tools have, along with the rapid progress of cancer genomics, generated an increasingly complex understanding of metabolic reprogramming in cancer. As numerous connections between oncogenic signalling pathways and metabolic activities emerge, the importance of metabolic reprogramming in cancer is being increasingly recognized. The identification of metabolic weaknesses of cancer cells has been used to create strategies for treating cancer, but there are still challenges to be faced in bringing the drugs that target cancer metabolism to the clinic.

Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells

Regulation of Intracellular pH in Human Melanoma: Potential Therapeutic Implications

Melanoma cells in vivo maintain intracellular pH (pHi) in a viable range despite an extracellular tumor pH (pHe) that is typically below 7.0. In general, three families of transporters are capable of removing metabolic protons, but the specific transporters responsible for the maintenance of pHi at low pHe in melanomas have not been identified. Although the transporters exist in most cells, an inhibitor would be predicted to have selectivity for cells located in an acidic tumor bed because cells in that environment would be expected to have transporters chronically activated. In this report, the levels and extent of expression of the Na+/H+ exchanger (NHE-1) and two of the H+-linked monocarboxylate transporters (MCTs) were evaluated in three melanoma cell lines. The effects of inhibitors of each transporter were tested at an extracellular pH (pHe) of 7.3, 6.7, or 6.5 in melanoma cells that were grown at pHe 7.3 or 6.7. The activity of MCT isoform 1 (MCT-1) was up-regulated in three melanoma cell lines at low pHe, but that of NHE-1 was not. Furthermore, NHE-1 activity was lower in the melanomas than in other normal and malignant cell lines that were tested. Reverse transcription-PCR using primers specific for MCT-1, MCT-4, and NHE-1 showed that expression of none of these transporters was reproducibly up-regulated at the level of transcription when cells were grown at pHe 6.7 instead of pHe 7.3.Ex vivo experiments using DB-1 human melanoma xenografts grown in severe combined immunodeficient mice found that MCT-1 and not NHE-1 was a major determinant of DB-1 tumor cell pHi. Taken together, the data indicate that MCTs are major determinants of pH regulation in melanoma. In contrast, keratinocytes and melanocytes under low pHeconditions relied on NHE-1. Inhibitors of MCTs thus have great potential to improve the effectiveness of chemotherapeutic drugs that work best at low pHi, such as alkylating agents and platinum-containing compounds, and they should be selective for cells in an acidic tumor bed. In most tissues, it is proposed that the NHE-1 could compensate for an inhibited MCT to prevent acidification, but in melanoma cells this did not occur. Therefore, MCT inhibitors may be particularly effective against malignant melanoma.

Quercetin, an Inhibitor of Lactate Transport and a Hyperthermic Sensitizer of HeLa Cells

The role of low intracellular or extracellular pH in sensitization to hyperthermia

Monocarboxylate transporters as potential therapeutic targets in breast cancer: inhibition studies in vitro models

Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as L-lactate. We previously reported that a-cyano-4- hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative controletreated cells. In this study, we demonstrated that MCT4 expression is associated with statininduced cytotoxicity.

Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

A new emerging hallmark of cancer: The pH gradient reversal

The pH gradient reversal can possibly be considered as the most distinct cancer specific event, occurring quite early. It is a mandatory event manifesting in all kinds of cancerous cells and tissues. It is essential for survival and proliferation of tumors. An alkaline, low salt diet with ample fruits and vegetables minimizes pH gradient reversal thereby reducing tumor aggressiveness and therapeutic resistance. This knowledge may be useful to replace the existing more toxic, non-selective therapies.

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

Bicarbonate increases tumor pH and inhibits spontaneous metastases.

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

Neutralizing tumor acidic environment improves immune-targeting therapies

Sodium bicarbonate combined with PD-1 or CTLA-4 Inhibitors or adoptive T-cell transfer reduces melanoma and pancreatic tumor growth. Cancer cells have the ability to grow in an acidic tumor environment that is detrimental to other cells, including immune cells. In a new article, researchers have reported that neutralizing the acidic tumor environment increases the efficacy of several immune-targeting cancer therapies.

Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy.

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

In Vivo Loss of Function Screening Reveals Carbonic Anhydrase IX as a Key Modulator of Tumor Initiating Potential in Primary Pancreatic Tumors.

Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.

The MCT4 Gene: a Novel, Potential Target for Therapy of Advanced Prostate Cancer.

MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer.

Cancer generated lactic acid: Novel therapeutic approach

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy

Macrophages and Energy Metabolism in Cancer: The Ketogenic Connection

Systems analysis of intracellular pH vulnerabilities for cancer therapy

A reverse pH gradient is a hallmark of cancer metabolism, manifested by extracellular acidosis and intracellular alkalization. While consequences of extracellular acidosis are known, the roles of intracellular alkalization are incompletely understood. By reconstructing and integrating enzymatic pH-dependent activity profiles into cell-specific genome-scale metabolic models, we develop a computational methodology that explores how intracellular pH (pHi) can modulate metabolism. We show that in silico, alkaline pHi maximizes cancer cell proliferation coupled to increased glycolysis and adaptation to hypoxia (i.e., the Warburg effect), whereas acidic pHi disables these adaptations and compromises tumor cell growth. We then systematically identify metabolic targets (GAPDH and GPI) with predicted amplified anti-cancer effects at acidic pHi, forming a novel therapeutic strategy. Experimental testing of this strategy in breast cancer cells reveals that it is particularly effective against aggressive phenotypes. Hence, this study suggests essential roles of pHi in cancer metabolism and provides a conceptual and computational framework for exploring pHi roles in other biomedical domains.

The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging.

Dichloroacetate induced intracellular acidification in glioblastoma: in vivo detection using AACID-CEST MRI at 9.4 Tesla.

In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide.

Topiramate induces acute intracellular acidification in glioblastoma.

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells.

Characterization of the mechanisms by which Carbonic Anhydrase IX facilitates tumour growth and metastasis

Therapeutic Targeting of Cancer Stem Cells: Integrating and Exploiting the Acidic Niche

Cancer stem cells (CSC) or tumor-initiating cells represent a small subpopulation of cells within the tumor bulk that share features with somatic stem cells, such as self-renewal and pluripotency. From a clinical point of view, CSC are thought to be the main drivers of tumor relapse in patients by supporting treatment resistance and dissemination to distant organs. Both genome instability and microenvironment-driven selection support tumor heterogeneity and enable the emergence of resistant cells with stem-like properties, when therapy is applied. Besides hypoxia and nutrient deprivation, acidosis is another selection barrier in the tumor microenvironment (TME) which provides a permissive niche to shape more aggressive and fitter cancer cell phenotypes. This review describes our current knowledge about the influence of the “acidic niche” on the stem-like phenotypic features of cancer cells. In addition, we briefly survey new therapeutic options that may help eradicate CSC by integrating and/or exploiting the acidic niche, and thereby contribute to prevent the occurrence of therapy resistance as well as metastatic dissemination.

Unexpected therapeutic effects of cisplatin

Cisplatin is a widely used chemotherapeutic agent that is clinically approved to fight both carcinomas and sarcomas. It has relatively high efficiency in treating ovarian cancers and metastatic testicular cancers. It is generally accepted that the major mechanism of cisplatin anti-cancer action is DNA damage. However, cisplatin is also effective in metastatic cancers and should, therefore, affect slow-cycling cancer stem cells in some way. In this review, we focused on the alternative effects of cisplatin that can support a good therapeutic response. First, attention was paid to the effects of cisplatin at the cellular level such as changes in intracellular pH and cellular mechanical properties. Alternative cellular targets of cisplatin, and the effects of cisplatin on cancer cell metabolism and ER stress were also discussed. Furthermore, the impacts of cisplatin on the tumor microenvironment and in the whole organism context were reviewed. In this review, we try to reveal possible causes of the unexpected effectiveness of this anti-cancer drug.

A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis

Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) studies. Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. Conclusion: Bicarbonate markedly enhances the anticancer activity of TACE.

pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma

Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.

A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis

Study design: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) studies. Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. Conclusion: Bicarbonate markedly enhances the anticancer activity of TACE.

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

Monocarboxylate transporters in cancer

Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT+/- and MCT-/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities

Although immunotherapy plays a significant role in tumor therapy, its efficacy is impaired by an immunosuppressive tumor microenvironment. A molecule that contributes to the protumor microenvironment is the metabolic product lactate. Lactate is produced in large amounts by cancer cells in response to either hypoxia or pseudohypoxia, and its presence in excess alters the normal functioning of immune cells. A key enzyme involved in lactate metabolism is lactate dehydrogenase (LDH). Elevated baseline LDH serum levels are associated with poor outcomes of current anticancer (immune) therapies, especially in patients with melanoma. Therefore, targeting LDH and other molecules involved in lactate metabolism might improve the efficacy of immune therapies. This review summarizes current knowledge about lactate metabolism and its role in the tumor microenvironment. Based on that information, we develop a rationale for deploying drugs that target lactate metabolism in combination with immune checkpoint inhibitors to overcome lactate-mediated immune escape of tumor cells.

The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasio

A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO(3)) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pK(a). This indicates that NaHCO(3), with a pK(a) of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pK(a) of approximately 7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion.

Drug resistance and cellular adaptation to tumor acidic pH microenvironment

Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological; emerging as a consequence of the tumor’s physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an “ion trapping” phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed.

How does tumor acidity help cancer spread?

Other references:

A nice long post on pH:


This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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116 thoughts on “pH in Cancer & Tumor Acidification: A Top Treatment Strategy

  1. Hi Daniel,

    Thanks for this remarkable article about the pH of tumor environment and your specific suggestions as to how to manipulate it. I am wondering about its relation to citric acid. How do these two paradigms (i.e.using e.g. sodium bicarbonate to alkalinize and using citric acid to prevent glycolysis) can be reconciled/used simultaneously?

  2. Hi Helga,

    Thank you. If we target glyco inhibition with Citric Acid and create a more alkaline environment with Sodium Bic the two will work well together as they would have different mechanism against cancer. What I do not know is if Sodium Bic would interfere with the availability of Citric Acid at the tumor site. On the other hand, if we believe that another mechanism through which Acids can work against cancer is by further lowering the extra cellular pH, Sodium Bic should be avoided as it works against that. All in all, I would probably not combine Sodium Bic with Citric Acid, just to be on the safe side due to above potential interactions.
    This is how I understand it Helga. I hope it answers your question.

    Kind regards,

  3. Hi Daniel,

    Thanks for your response. I was inclined to also avoid sodium bicarbonate for now. As I said on the citric acid thread, I found some omeprazole at home and took one. Now am going into the infra sauna to work up some sweat.

    Kind regards,

    1. Hi Helga,

      I answered your question about the Omeprazole dose in another place but just to make sure we have the answer also on this pH related page, I will post the comment here too. This is just to have a feeling on the dose that has been seen effective against cancer when given with chemo:

      First, I should say Lanzoprazole seems to be more effective than Omeprazole (I will later search for the reference). Next, here is a very relevant study performed on dogs showing how the administration of high dose Lanzoprazole next to Chemo lead to extreme increase of chemo effectiveness (partial or complete responses in 67.6% cases using Lanzoprazole, vs. 17% who experienced only short lived partial responses in the control group): In this case they used 5mg/kg/day during 3 days, followed by four days at the dose of 1 mg/Kg/day to prevent gastric hyperacidity rebound.

      Assuming this conversion factor I would assume that the human dose would be half of that used for dogs, i.e. 2.5mg/kg/day for 3 days during chemo and 0.5mg/day for the four days after that.

      Kind regards,

      1. What are the potential side effects of high dose lansoprazole ?

        also for a patient who have high blood calcium levels , is it safe for him to try high dose lansoprazole ?

        I tried lansoprazole in a dose range of 60mg to 80mg / day

        but never tried 200mg / day

        if it may help chemo , I will be happy to try it

        1. That is a good question Emad. I think it will be not so difficult to find your answers if you do a bit of research on that. If you find more info please post it here too. I am sure there are many studies on the safety of Omeprazole and Lanzoprazole. For example, just a quick search indicates the following for a specific disease: “The recommended initial dose is 60 mg once daily. The dose should be individually adjusted and the treatment should be continued for as long as necessary. Daily doses of up to 180 mg have been used. If the required daily dose exceeds 120 mg, it should be given in two divided doses.”

        2. Maybe combine with vitamin K2 if you have high calcium-levels. Check that up if my memory is correct k2 should be able to prevent hypercalcemia.

          1. thank you very much Daniel and Andreas

            K2 should be good for hypercalcemia , my mother will supplement on it soon

            hope you are all doing good 🙂

  4. I can confirm lansoprazole working well with weekly nab-paclitaxel (at suboptimal dose on it’s own) and omeprazole with metronomic cyclophosphamide + etoposide + celecoxib.

      1. Yes, real life. Unfortunately nab-paclitaxel was too expensive for a long term option (400 mg per month was about 1700 euros) and metronomic plus omeprazole wasn’t initially clear if working (without celecoxib and omeprazole it didn’t).

        1. I am sorry to hear the financial limitations were the reason not to be able to continue with a treatment that was showing results. I think this is a very valuable piece of information. Can you please explain what was the tumor type, the treatment used and how that was used (e.g. timing, dose) and the observed results? Thanks in advance.

          1. That happened over 4 years ago, so some details may be inaccurate. The cancer type was metastatic NSCLC that became refractory to Carboplatin and Taxol or Carboplatin and Vinorelbine. Keep in mind that a lot of new articles were published since, I didn’t have today’s knowledge.
            IIRC the lansoprazole was given as a pre-treatment before the Carboplatin (every 3 weeks, probably useless by that time), and Abraxane weekly. Progress was measured by weekly blood test, evolution of the CEA marker.
            The best response was about 10% reduction in CEA weekly when the high dose lansoprazole was given before the Abraxane (each week). But the oncologist believed that the cancer became sensitive again to paclitaxel (which proved wrong) and my father was approved to be given Erlotinib (which turned out a disaster), paid by the insurance. I could have afforded to pay for another couple of months of Abraxane, but my father didn’t want me to.

            1. Thank you Ovidiu! What was the dose of Lansoprazole that was given and how long before the chemo?
              (Again) I am really sorry to hear about your dear father, Ovidiu.

            2. IIRC the high dose was 120 mg the morning before the chemo (which usually was late evening) and then 30 mg daily for a couple of days after.
              Also IIRC the best reduction in CEA was when the chemo was delayed for a day and there were 2 days of 120 mg before Abraxane (suboptimal dose 100 mg, optimal should have been 140 mg).
              My idea was to have get the cytotoxic result from Carboplatin (pre-treated with lansoprazole) and then the next 3 weeks to stall the cancer with Abraxane.
              It turned out the best results were from Abraxane + lansoprazole instead, by then resistance to Carboplatin was too high.
              A couple of years later I found this: Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma

            3. Thank you Ovidiu! This is very clear and helpful for many.
              I always had a very good feeling regarding this strategy. Adding more proton pump inhibitors (such as Amiloride) next to Lanzoprazole should further help Chemo or Radiation.

            4. I don’t know for how long the high dose lansoprazole can be taken. Before giving it to my father I tested it on myself and there was some nausea / uneasy feeling.
              Also PPIs and cimetidine shouldn’t be used with erlotinib (this was not the case for my father).
              Gastric Acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer.

            5. Thank you. Very good point Ovidiu. If the chemo is given orally, we need to check how the other drugs and supplements may affect its absorption and availability at the tumor location.

            6. Ovidiu, i understand you and your father are fighting Lung Cancer?
              If so me and my mother are fighting it too. Some advice or guidance from your own experience would be much appreciated. I am kinda new here and apparently don’t have as much knoledge as you do.
              My mother is against chemo due to the belief that it will only cause more harm than good.

              Please let me know.
              My best wishes to you.

            7. @Alex: my father died in December 2012, the knowledge I accumulated trying to help him didn’t make much difference.
              As for advice for your mother, please first post some info on the cancer type. Is it NSCLC or other kind? Is she a smoker? Did you perform tests on the resected tumor to determine the onco-protein(s) involved (like EGFR, HER2, KRas, ALK)? Is the metastasis still limited to the lung(s) or has spread to lymph nodes and other organs (this is visible on a CT scan)?

  5. The issue of Seminars in Biology in which D’s recent article appeared also had this.
    Very interesting, very focused acidification of tumor cells resulting in tumor clearance.
    Focal photodynamic intracellular acidification as a cancer therapeutic, Semin Cancer Biol (2017)

  6. Is this body ph even a thing? What about stomach acid? It all sounds cute and great, a little baking soda, some salt…. magic bullet….
    No disrespect but, it’s confusing for me and probably the vast majority of people
    Then there’s the other side claiming that the body can not and should not be alkaline, that in fact the body constantly invests energy to keep ph levels as they are.

    PS, was watching a video on natural remedies and got cut by radiation therapy commercial….. big business!
    I’ll leave that to your private opinion, mine if you should ask is…. not good.

    Thank you,

    1. Hi Alex,

      Body pH is a fact and unbalanced pH within the tumor cells and around the tumors are just facts. There is no question about that as there is a huge amount of science supporting that. Nobody in academic world is questioning that.

      What is indeed questionable is the alkaline diet or baking soda promoted as the cancer cure.

      Personally, I like the alkaline diet not because of its name but because of the healthy components of this diet. Just that.
      Regarding backing soda, I do not know what is really the effectiveness and impact of that on the body pH. What I know, is that when administered IV, the impact can be relatively large on the pH and may also affect the pH around the tumors which would be positive for e.g. immune system, due to the way how T cells, DC, macrophages and other immune cells are activated and impacted by pH. However, I have a bit of strange feeling regarding IV bicarbonate to achieve pH modulation around the tumor and I do like and believe much more in the effectiveness of the strategy discussed above.

      I hope this helps and clarifies a bit the subject.

      Kind regards,

      1. Thank you dear Daniel.
        Good news here. DCA Arrived today, Mom is feeling better.
        Still didn’t give mom any DCA, and eased down on metformin.
        I would like to know what is your starting dosage recomendation for DCA and if we should stop to 1g/day or more if possible.
        Also 1g/day in one dose or spread in 2.
        Blood tests performed before this recent treatment are showing a slight increase in markers and some decreases in the chemistry part.
        CEA 46.74 – out of range
        CA 19-9 20.2 – still in range

        Seric Creatinine 0,61
        CRP Quantitative 17.14 – out of range
        Fibrinogen 479.39 – out of range
        LDH 167
        TGO/AST – TGP/ALT decreased
        Seric Urea – Decreased 24->20

        Thank you very very much.

  7. If i remember correctly, Simoncini did not promote the idea of ingesting of baking soda but did promote the IV or tumor injection or baking soda.
    I also agree with the nutritional value of the “alkaline diet” but not with the goal of getting the body “alkaline”
    As for achieving ph levels in the blood hostile to tumors. i’m under the asumtion that the mechanism of action was more oriented towards osmosis of tumor tissue liquids.
    I could all be wrong about all this, if so, i am sorry for wasting time.
    A few things i would like to ask is what about vitamin k? There are many documented cases of “spontaneous” remission. I’m wondering if clotting of vital blood veins would have a possible role there. And if so, as with snake venom, would it make sense to try something like that? I understand there could be serious consequences. But the tumour itself sounds like it would make it easy since the blood around it is thicker than normal from what i understand, in theory, making it easy and less risky.
    Just exploring some ideas and thoughts, nothing more.
    All this reading got me seeing that the immune system can’t really tell there’s something very dangerous there, not enough to launch a full attack and then begin to eat at it, a trigger may be needed….
    It can’t see that the tumor is non-self because the tumor is very very very similar to self, i know there’s a lot to talk about there if you get into technicals but i won’t and i can’t. Sorry for my lack of knoledge but i try. Don’t wish to sound arogant or ignorant.
    I come humble and willing to learn within the limits of my understanding.
    My questions can be silly sometimes but i feel that questions also add value to what we are trying to do.
    I’ve been offered a possible chance to have a vaccine done from a tumor sample taken trough puncture. I don’t know weather this would help in reality or not, this is when your vast experience comes in play again. I know in theory things work nice and perfect, but you are more aware of the reality of these treatments.

    Thank you for doing all this for all of us, i am sure Mihaela would be proud, and i hope your mother knows how lucky she is to have given birth to such a great man who is trying to solve the world’s most problematic medical issue.
    Have a good evening,
    Alex & Mother.

    1. Hi Alex,

      you don’t want to “clot” the veins as that clot might travel to unwanted regions of the body and cause embolism. What you want to do instead is anti-angiogenesis, i.e. cut off the blood supply of the tumors. If you type in google “anti-angiogenesis natural products” you’ll get many hits and a list up front:
      4.1 Herbs and Phytochemicals
      4.1.1 Artemisia annua (Chinese Wormwood) …
      4.1.2 Viscum album (European Mistletoe) …
      4.1.3 Curcuma longa (Curcumin) …
      4.1.4 Scutellaria baicalensis (Chinese Skullcap) …
      4.1.5 Resveratrol and Proanthocyanidin (Grape Seed Extract) …
      4.1.6 Magnolia officinalis (Chinese Magnolia Tree)
      More items…

      Also, regarding the immune system, sy said (maybe Alberto) that lactic acid suppresses the immune system. That is one reason to consume citric acid because it suppresses fermentation and therefore production of lactic acid. This in itself is beneficial for the immune system.

      It is a good thing and a healthy attitude you ask questions here.

      1. As always,
        Thank you so much Helga.
        You may notice i come back to these late, yes i’ve ben very very very busy and will continue to be sadly. But i am making progress.
        Please let me know if you would like any help with anything you may not find in your area as i live in Romania and some things can be found cheaper here depending on many factors. I also have technical skills when it comes to computers and some other appliances.
        As a friend i offer my help when needed.
        Always Available on Skype Snake_Systems

        1. Dear Alex,

          Thanks so much for your kind offer. You are a very good person. I hope your mom continues to be doing well.

          Kind regards,
          ps. I wonder what do you do work-wise? Apparently computer-related but am just curious what exactly you do 🙂

          1. Dear Helga,
            Music was my first love and that lead to me learning english sincer kindergarden, i admit i am not what i used to be when it comes to both. Growing up to be an adult man has it’s “side-effects”. And you kinda loose skills, lack of practice, interest,
            Because of music i learned some basic electronics to make things sound louder of apply filters to the sound, mix it.
            Meanwhile i discovered the computer in it’s relatively primitive form, tape storage, keyboard, tv screen, old stuff. Even then
            This must have been in the early 90’s. And i took interest in the computers due to their ability to play sounds.
            Also as a kid i was also interested in playing those games i could get my hands on,
            Over time despite the limited financial restrictions, i’ve learned how to fix computers and in my 20’s i wanted to get my own IT company going since i was so successful as a freelancer and have accumulated a lot of reputation till 2008.
            Destiny has made so that the recession also came then, along with people’s drop in interest for PC’s and switching to mobile.
            I couldn’t get money from a bank and even if i did, the market was dropping fast.
            Had some jobs but they didn’t last much sadly. Life always hit me hard from all sides, i’m in a village, i like it here now.
            But it’s not what i wanted and expected from me and life. I should have been running a great IT company called Snake Systems…. who knows…. one day.
            Nowadays i’m a university student, and i work at home in a virtual world called Second Life where virtual currency can be converted into real currency $.
            This virtual world offers plenty of business options, selling virtual land, services, others. My computer skills are useful there and not just that. It’s a matter of using your own imagination to come up with profit.
            Income wise it’s not much, it used to be enough for me, before this cancer.
            I work there because i have no actual alternatives, especially now when i rather be with mom than to commute to some job at the supermarket in the city where they would let me go in 2 months, as they do with so many.
            As for the student part, being 32, knowing you gave up on so many things in the past in the name of love, looking back and seeing those wrong choices, i wanna prove to everyone else around me i am not stupid or uneducated and that it’s never too late to do it., i just made the wrong choices for things i thought were more important to me at that time.
            I don’t want to be underestimated just because i lack a degree. I am more than just a paper, but if the paper will prove it. I will have it. And when i get it i will make multiple copies to share with everyone who has underestimated me in that matter. Company owners, former co-workers, “friends”, former girlfriends who would mock me, relatives.
            And yet again i am being dumped by the gf, when you have problems, the people who say that they love you, may show that they don’t understand anything and they rather not deal with your problems and they leave. Despite the “i love you”.
            Single 4 life LOL… rather be single than to live a life full of deception.
            What can i say…. i think this answers your questions 🙂 more or less.
            Do take care please.

            1. Thank you,
              I hope that i can get my mom feeling well and then we can all look back and laugh, having learned a lot so that maybe we too can help others in need and willing to receive the help and fight the fight, ready to succeed but also fail.
              There is nothing i dream more than this now
              Thank you very much for everything.

  8. Daniel how large dose of ibuprofen would be required to inhibit the mct4 ? Do you have any idea of that ? Since ibuprofen is a bit toxic one need to be a bit careful.

    1. Dear Andreas,

      Thank you for the very good question. I do not have a clear answer for Ibuprofen dosage required to inhibit MCT4 but I have an answer for others NSAIDs dosage require to inhibit MCT1.
      This however can give us an idea if the typical NSAIDs and their typical dosage is close of far from MCT inhibition, and the answer is a nice one, i.e. typical dosage of NSAIDs is effective in inhibiting MCTs.
      I am happy you asked this question because as a result, I found this great reference stating the following:

      The inhibitory concentrations of tested NSAIDs (diflunisal, mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid) are in the range of physiologically relevant concentrations that are achievable from the oral intake. For example, the suggested dosage range of diflunisal is 500 mg to 1000 mg daily for osteoarthritis and rheumatoid arthritis. The peak plasma concentration of diflunisal achievable from single 500 mg oral dose was 87 ug/mL, while the Ki of diflunisal is 29.56 uM (equivalent to 7.40 ug/mL). Therefore, a strong inhibition of NSAIDs on MCT1 is achievable at the relevant plasma concentrations of diflunisal.

      Three NSAIDs, namely diclofenac, meclofenamic acid and tolfenamic acid exhibited strong inhibitory effects on L-lactate transport, with a Ki value of 6.17 uM (~1.96 ug/mL), 9.97 uM (~ 3.35 ug/mL) and 8.95 uM (~ 2.34 ug/mL), respectively. The recommended dosage for diclofenac is 100-150 mg/day in divided doses for the relief of osteoarthritis. The peak plasma concentration of diclofenac achievable from single oral 50 mg dose is 0.8 ug/mL, while the peak plasma level of diclofenac achievable from multiple doses (oral 50 mg was administered 3 times daily for 7 days) was 2.3 ug/mL [218]. The recommended dosage of meclofenamate sodium for pain relief, arthritis and osteoarthritis is 200 to 400 mg daily, administered in three or four equal doses. After the administration of 100 mg meclofenamate sodium for 18 days every 8 hours, the peak concentration was 4.8 ug/mL for the parent compound on both day 1 and day 18. Lastly, tolfenamate is subscribed to patients suffering from acute migraine with a recommended dosage of 200mg. Pharmocokinetics data shows that a single oral dose of 200 mg, 400 mg and 800 mg of tolfenamic acid achieved a peak concentration of 2.97 ug/mL, 6.15 ug/mL and 12.2 ug/mL in the plasma, respectively [219]. Taking this data together, it suggests that strong inhibition of NSAIDs on L-lactate transport on human erythrocyte is expected at the therapeutically relevant plasma concentrations of tested NSAIDs.”

      Since all of the above are good MCT1 inhibitors we can expect that all of them will have important anticancer effects. For example, I did not know tolfenamic acid, and now that I jut check shortly on google and this is the result:

  9. Thanks Daniel, that’s good news.
    I am glad that I can be to some help sometimes to 😉 sometimes a simple question can open up new line of thoughts.
    Anyway maybe diclofenac is a better choice than ibuprofen.

          1. Yes one can be lucky to find the right substance, for example I have read that one person with pancreatic cancer did control it with only curcumin and gemcitabine, for at least 18 month, which is very long time with this aggressive cancer. Every tumor is unique.
            I also believe to find the right synergies between different substances. I believe it’s harder for the cancer to become resistant if it’s attacked in different ways.

            1. Very impressive.
              I’m borrowing a theory that one of the main reasons some treatments may not work when they work for others.
              That theory is based on autoimmune disease. An imbalance of the immune system that likely allowed the cancer to form in the first place and that some treatments may actually favor the wrong side of the immune system, the one that is already at nominal levels. This is where chemo would possibly help, but then again i feel a more smart solution should and must exist.


            2. HI Alex. What do you mean by autoimmune disease? I am not sure if I understand what is its role in the points you mentioned above.

            3. Well i watched a video a while back, from a non-doctor.
              He was saying that the Gerson may actually do the cancer a favor. That it’s important to check glands, liver, cell counts etc. To do more and more tests to determine the right treatment.
              Same would go for any other protocol, that whatever worked for someone, will possibly fail for another or do worse due to autoimmunity.
              He was saying that there is no CURE because cancer has too many starting points as options and so many routes, that it ends up being something else even from the start.
              He was saying we know a lot about cancer but we’re not making the treatment a per/person thing.
              Indeed there seems to be a rush like the line in a supermarket… very very little special individual treatment.
              We seek the fast, easy, cheap solution with the most profit. I’m all too sure you know about all that.
              I’m thinking that maybe mother has an autoimmune disease. She had abnormal bone growth in her knees, a year before diagnosis, this lead her to believe it may be a similar problem in her back, but it wasn’t…….

              Many Many Thanks!

            4. Hello Alex
              Yes tricky question, as a layman what I’ve understand is that ALS, MS and common allergia, is autoimmune deseases. That the immune system is somehow overactive and sometimes attacking the body’s own tissues.
              About allergia I have heard conflicting reports that people with allergia have lesser incidents of cancer due to the overactive immune system. But I have also heard the opposite.
              Personally I have come to like the explanation that inflammation cause some cancers, this is maybe not contradicts your theory, at least inflammation seems to be a strong driving force.
              Anyway the cause of cancer starts a chain of failures in the body and it can be hard to indentify the root cause. One can perhaps just look on one chain on event believing it’s the cause of the cancer.

            5. Yes…. inflamation.
              If we could only put ice on it… and then sprinkle it with table salt. Wait for fluid exchange, freeze it, melt it, wash it. done. Just add ginger. Ehhhh….

  10. Hi Daniel,

    I actually started to read your article above and must say again, really impressed! Have you published this actually in a journal (or was that something else, someone seemed to say you published an article in a journal)? This is brilliantly thematic and well-thought-up about various aspects of the pH around and in the tumor. I haven’t finished it reading yet. So it seems there are quite a few drugs that are/can be repurposed as cancer treatments. What I found scary was the story about the amiloride and ovarian cancer

    They found a metastasis in the leg muscle of the patient?! Never heard of such a thing. Anyway, I encourage others as well to take their time and read this article. It is simply brilliant!

    1. Dear Helga,

      Thank you very much for the appreciation. I also very much like this strategy. And what is interesting is to see that this perspective (pH modulation) captures a large of the drugs that are known to work against cancer. So this may be a central mechanism while the other mechanisms identified on the same drugs may just be a result of pH modulation (which is known to lead to various intracellular enzyme inhibition or activation, etc.). I will send to you the PDF of the article by e-mail.

      Kind regards,

    2. Dear Helga,

      Amiloride is really interesting.Because of my poor language,i searched it in my own language.
      It says it is used for edema which the cause of hypertension,low pumping heart or liver cirrhosis.
      It protects potassium so we should be VERY careful.
      But you are right ,it deserves more searching.

      Kind Regards

    3. hi Helga,

      regarding repurposed drugs to fight cancer you can also check what drugs Ben Williams used to beat terminal glioblastoma.
      Since then others with GB used similar cocktails with success. these are drugs againts asthma, ace, hearburtn… all pretty boring stuff. Again, i dont think most oncologists are aware of his approach (or care about) and they dont propose this – totally safe- method for terminally ill brain cancer patients with no chance to survive.

      Even B Williams remembers that one of his drugs told him he could hurt himself with these drugs.. then the doctor started to laugh and apologised.

      Of course this evidence is anecdotical, HOWEVER, almost each drug in the cocktail has demonstrated anti cancer potential so in this context i am sure Ben W and his followers would not be here without the cocktail.

      Also, long term survival is extremely rare in GB.

  11. Dear Daniel,

    I found your article on ResearchGate and just downloaded it, thanks! I had no knowledge about this journal. Will read it on the bus. Thanks again! How did you find your coauthors, I wonder?

    Kind regards,

    1. Hi Helga,

      I was not aiming for publishing in scientific journal, but my focus was always on finding ways to help my dear wife. IN that context I came in contact with the authors, who are both great scientists, doctors and great humans at the same time. We exchanged ideas, we resonated and they asked if I like to join in writing the review. That is the story on short behind that very nice review. More valuable than being part of the team writing the review is that I feel honored to maintain the contact with the authors who have a long history in the battle against cancer. I hope I can intensify that once I will be able to allocate more time to the oncology field. I will also response asap to your e-mail – it has a star on it as a reminder to respond 🙂
      We can also explore the options to use our network in creating scientific content by connecting the existing scientific work to gain new perspectives.

      Kind regards,

      1. Dear Daniel,

        My friend has problems with acid reflux since 2000’s.She has been using lansoprazole 30 mg/day But modest effect.
        Than she found Esomeprazole.
        It has better effect on stomach acid which she experienced in real life.
        May be it is better than lansoprazole on also proton pump inhibition of cancer cells.
        Do we have any data on that?
        And i couldnt find cimeditine,it is out of production.Do we have any similar drug?
        Kind Regards

        1. Dear Ergin,
          Based on extensive research from Italy, Lansoprazole seems to be the most effective. I have to find the reference but I also receive that via private communications from the researchers.
          Cimetidine is available on e-bay as is an over the counter drug in USA (Tagamed) and in Asia. In Germany you can get it from pharmacy but on prescription from your doctor.
          Kind regards,

          1. Thanks Daniel,

            I called her and learned that Esomeprazole is 40 mg tablets.Lansoprazole is 30mg.
            Small difference but big result in stomach acid inhibition.And may be after 16 years lansoprazole became resistant.
            Just an idea,can we use both before chemo?
            Kind Regards

  12. Too much sodium and not enough potassium in our modern diet (also at the cellular level)! I prefer to use potassium bicarbonate instead of sodium bicarbonate! What do you think of this hypothesis?

    1. High potassium may also be an issue and fuel the tumors as well as sodium. In addition I would not use bicarbonate as long term strategy but only as IV before immunotherapy or chemotherapy (if chemo is weak base which seems to be common for many chemo). Evidence is building up suggesting that tumor may grow faster in an alkaline environment compared to acidic one. As a result, I think long term administration of sodium bicarbonate or other forms, may be the wrong approach, specifically when the tumors are large. Unfortunately, that is my conclusion at this point. I am saying unfortunately, because I did believed and would like to believe in sodium bic benefits.

  13. Hi Daniel,

    In regards to our talk about platins and PPIs, this source states that cell lines were sensitized to cisplatin after pretreatment with PPIs, likely indicating that cisplatin is a weak base:

    I’m not 100% if this would translate to carboplatin as the two have pretty different chemical compositions. The main similarity is the two NH3 groups bonding to the Pt. Apart from this, cisplatin has just two chlorine molecules bonded to it, while carboplatin is more complex.

  14. Cancer cells exposed to γ-tocotrienol treatment displayed a significant decrease in MCT-1 levels and a corresponding reduction in lactate production. (4~8 µM)

    450 mg γ-Tocotrienol has superior bioavailability in healthy human subjects. (Cmax : 13~20 µM ; Tmax : 4.7~5.6 h)
    (γ-Tocotrienol Molar mass 410.6 g/mol)

  15. Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O 2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth.

    The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target.

  16. Guys I am completely agree about the importance of pH in cancer progession. Here we are talking about different ways to alkalinise the body. But let me tell you something the best way to do is with a machine called kagen, you can clean your food and also drink water continuosly with a pH of 11, this pH water is similar to Lourdes water where a lot miracles happen you are giving to your body also electrons to regulizar membrane cells

    1. Hi Alberto,

      Thanks for the comment.
      The above post is focused on ways to induce the accumulation of acidity inside the cancer cells. This can lead to cancer cell death. The “side effect” is that the body becomes more alkaline, which is also good for the immune system and others. Alkalinity of the body can indeed be achieved in multiple ways but I think this approach alone has potential only for early cancers or small tumors. For advanced cancers, when tumors are larger on the other hand I expect inducing alkalinity of the body with diet or water will only have limited impact on the tumors. This is why, for advanced cancers I would turn my attention to proton pump inhibitors and other ways to increase the intra cellular acidity, which is a more aggressive approach.

      If we only want to focus on alaklinity of the body for advanced cancers, we may consider Sodium Bicarbonate. But to my knowledge in some cases that may also lead to growth of the tumors so I would only used it prior to immunotheraphy or weak base chemotherapy.

      Kind regards,

    1. I read an article about how to potantiate antibiotic effectiveness with proton pump inhibitors.

      The real war is begining Alex.If i can not do my duty,i wont forgive myself.I need all help from now on.Help for thinking logically.We already know lots of mechanisms by Daniel’s help.I have no computer here,so skype.

  17. Hi Daniel- I wanted to thank you for this very complete and practical article. We are actually familiar with the Advanced Medical Therapeutics clinic you mention above as it is a short drive up the road from us. We did visit with the doctor who runs it and found him to be both compassionate and brilliant. Ultimately we decided not to work with him for the moment as my husband is in NED and, with my medical background (Naturopathic Physician), we are able to do many therapies and use many medications ourselves. However, we would definitely consider using his services if we need to in the future. I believe he also works to some extent with Dr. Jason Williams and does work with 3BP combined with Salinomycin in Columbia. Anyhow, the information in this article is going in my “just in case” folder as it is good to have a variety of different strategies when and if we need them.

    (husband has stage IV prostate cancer, currently in NED with androgen deprivation)

  18. dear Daniel,
    Hope your doing Ok!

    With regard to this option for treatment strategy by influencing cancer cell/ cell environment acidity and more specifically the “pH and Chemo” section:
    Does Temozolomide (TMZ) and Lomustine (CCNU), which are alkylating agents used for GBM brain cancer, considered as weak acids and thus this strategy should to be avoided to prevent possible downgrading of the chemo activity?

    Many thanks for your help!

  19. Hi all, great article! I just can’t find my chemo-type, if it’s alkalic or basic. The chemo is called Kadcyla or TDM-1. Trastuzumab emtansine (TDM1) is a combination of trastuzumab and a chemotherapy drug called DM1. Anyone knows? Thanks, Charlotte

    1. Hi Charlotte,

      Thank you. I am not sure what is the profile of that and its not easy to find it. So the best is to contact some scientists that you find writing about this drug in the scientific articles on Pubmed, or contact the company that is producing the drug – say that you are a patient and that you would need to know if the drug has a weak-acid or weak-base profile.

      Kind regards,

  20. Hi Daniel
    Should the resultant Ph of chemo drug mix be considered (if there are more than one drug administered at same time) or each drug must be considered alone?

    There is a paper that might be interesting (dated back to 1990):
    “Acute tumor lysis syndrome and treatment response in patients treated for refractory chronic lymphocytic leukemia with short-course, high-dose cytosine arabinoside, cisplatin, and etoposide.”

    The authors saw four patients who developed acute tumor lysis syndrome when treated for advanced-stage, refractory chronic lymphocytic leukemia (CLL) with an initial cycle of cytosine arabinoside (Ara-C) 2 g/m2 every 12 hours x 4, cisplatin 35 mg/m2 every 24 hours x 2, and etoposide 100 mg/m2 every 24 hours x 2 (ACE).
    With aggressive hydration, urine alkalinization, forced diuresis, and high-dose allopurinol, acute tumor lysis syndrome was not seen in three subsequent cases of CLL treated with ACE.
    Of the eight patients, three are alive: one in a complete remission greater than 2 years, one in partial remission after three cycles of ACE, and one in Richter’s transformation to large cell lymphoma. The remaining patients died after one cycle of ACE chemotherapy, one as a direct complication of acute tumor lysis and pancytopenia, and four others from complications of severe pancytopenia and general debilitation. Therefore, ACE appears to cause a rapid dissolution of tumor cells in CLL, and with appropriate aggressive management of the tumor lysis and infectious complications may have a favorable impact on survival in advanced CLL.

    Unfortunately full text isn’t available.

    Kind Regards

    1. Hi Asafsh,

      I am not sure if I understand the question correctly but, indeed I would consider the provile of each drug specifically in the context of pH.
      If you need the paper and you cannot access please let me know and I will send it to you by e-mail.

      Kind regards,

      1. Dear Daniel

        Thanks for answer and clarification on drug Ph question.

        I don’t think i can use this paper in the treatment. That requires quite expertise in the field and proper setup.
        The paper was posted with thoughts that it could be relevant to the alkalinisation of extracellular Ph described in this article.
        afaiu, they achieved tumor lysis in 4 out of 8 patients (50%) by means of hydration, urine alkalinization, forced diuresis and high dose allopurinol.

        Kind regards

        1. Hi Asafsh,

          Ah now I understand your point. Actually they used a combo of chemo that lead to strong tumor lysis (TLS) that can be lethal. In order to protect and rescue the patients they frighted against TLS with hydration, etc. So the purpose was not alkalization to increase the effectiveness of chemo but to fight the outcome of chemo, i.e. intensive cancer cell breakdown (TLS).
          Here I discussed this subject shortly many years ago and how to address

          Kind regards,

            1. Hi Asaf,

              You are very welcome. I read the article in the link in the following way:

              1. Chloroquine intercalates into DNA and protects cells against topoisomerase II. So Chloroquine is an antagonist of Etoposide
              2. Because Chloroquine is weak base, it will not be absorbed by the tumors as it is protonated outside the tumor due to low pH (high acidity) around the tumors
              3. However, Chloroquine will enter normal cells (that are not surrounded by acidity) and protect them against Etoposite
              4. Based on the above, the authors propose to use this concept and give Chloroquine to patients going for Etoposite treatments (or other top II inhibitors) to protect them against side effects from Etoposide
              5. Furthermore, you could also imagine being able to increase the Etoposide dose as the good cells will be protected by Choloroquine
              6. But in order to achive such result (and protection against etoposide) very high doses of Chloroquine will be required, that may be toxic in humans
              7. As a result, the authors propose other substances that may do the job

              So in this paper, authors are not changing the pH of the tumors. Instead, they use the pH difference between normal and cancer cells to propose a new concept of using chemo in a way that would increase it’s effectiveness (with increased dose) and decrease it’s side effect.

              I find this concept very interesting since it may also work for natural substances, that could penetrate normal cells and defend them but cannot penetrate tumor cells due to the pH. In that way we could use those natural substances together with chemo without being afraid of inhibiting chemo effectiveness.

              Actually, I never looked at supplements from this perspective, i.e. their dynamics as a function of pH.

              Kind regards,

  21. Dear Daniel

    Thank you very much again for clarification.
    My error – I didn’t formulate question correctly.
    I meant that in paper about chloroquine etoposide ineraction ( there is etoposide vs Ph efficacy presented as percentage of survived cells vs extracellular Ph (Fig 2 (a)) where it is visible that increase of Ph resulted in much lower percentage of survived cell upon etoposide only administration ( (a) contains all – etoposide, chloroquine and etoposide + chloroquine combined graphs).
    i supposed that physicians who were trying to avoid complications from tumor lysis in article ( by using alkalinization could get unwanted cell death rate effect from higher than normal etoposide efficacy due to higher Ph(e) resulted from alkalinization (they used alkalinization to prevent from possible tumor lysis adverse effect, as you kindly explained before) and this alkalinization lead even to more tumor cell death rate and higher lysis effect, whose adverse effect couldn’t be managed by alkalinization itself.

    Kind Regards

    1. Hi Asaf,

      OK. Clear. Yes, that is a very good point. It’s very possible indeed that the alkalinization increased even more the effectiveness of Etoposide.

      Btw, to further increase the effectiveness of Etoposide, it would help to lower lower the acidity of intra cellular organelles ClC-3 inhibitors help on this line, as well as H(+)-ATPase inhibitors. Choloroquine and Niclosamide also work on this line – Chloroquine we discussed. Niclosamide is a great one but it’s difficult to get to the required levels specifically in tumours located in the head area (which is of interest here).

      Kind regards,

  22. Dear Daniel

    I will make stupid assumption, or may be re-invent that bicycle again.
    Does Ph gradient create difference in electric charge between intra and extracelllular space? Does this charge difference prevents drug molecules to enter tumor cells?
    The article “pH and drug resistance in tumors Natarajan Raghunand, Robert J. Gillies talks about ion trapping hypothesis.
    Could usage of low electric fields help chemodrug to enter tumor as it did in glioblastoma case?
    Below article may be gives an answer to that:
    Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

    So it might be feasible to add ttfields to the toolbox of PH gradient therapy when tumor sites can be exposed to its actuators.

    btw, the article on murine nano-silver research posted today says that:
    “It was hypothesized that the aggregation of NPs stimulated by a tumor microenvironment can be utilized to enhance the
    retention and cellular uptake of NPs in tumors. AgNPs (approximately 10 nm) showed a fast, sensitive, and reversible
    response to the pH change from pH 7.4 to pH 6.5, which enabled the AgNPs to be well dispersed at pH 7.4, while quickly
    aggregating at pH 6.5. The MSA-AgNPs were found to be stable at the pH of blood and normal tissues and thus exhibited an
    excellent stealth ability to resist uptake by macrophages; however, the MSA-AgNPs aggregated instantly in response to the
    acidic extracellular pH of solid tumors, leading to greatly enhanced uptake by cancer cells.42”

    if that is true, can silver assisted drug deliveries be done?

    p.s. If you remember Ergin had been mentioned synergy between chemo and silver in one of his posts, though it isn’t known whether both were used at same time.

  23. Will high doses ascorbic acid also contribute to lowering the pHi? It seems logical to me that having an acid taken into the cell will increase it’s acidity, but I don’t really know the scale.

    I have a family member with stage-4 colon cancer with substantial tumor burden in the liver, and he has been using IV ascorbic acid. He says he feels better from it. I was thinking that by inhibiting the proton pumps, there would be a larger build up of acidity within the cells and for a longer time.

    Is that a reasonable way to improve the therapeutic effect?

    1. Dear Rtyu,

      Thank you for your question, That is indeed a good question – I did not study that aspect of Vitamin C but when I have time I will look into that. If you find any relevant info on that line faster, please let me know.

      Until we clarify that, two strategies that are relevant to Vitamin C are these:

      Kind regards,

      1. Hi Daniel,

        I found something:

        They did an experiment showing that rate at which pHi increases depends on vitamin C concentration. Low concentrations of vitamin C (100µM and 1mM) allow faster pH increase, but at 10mM, the pHi stayed acidic for a longer time.

        The experiments were done on healthy rat colonic crypts, so there’s still a possibility that cancer cells have a different reaction. But I think it shows that there could be a benefit in combining high-dose intravenous vitamin C with the Intracellular Acidification strategy.

        1. Hi Rtyu,

          You found a very nice study! Thanks a lot! It’s amazing to see how all these anti-cancer drugs and supplements meet together and act coherently from several points of view, such as lowering intra-cellular pH, increasing Reactive Oxygen Species, or “starving” cancer by inhibiting energy-production.

          I like a lot the paper and I will now send it to an expert working for long time in the field of pH and cancer – this will make him happy too .

          Btw, it’s very nice to see how you started with a simple and natural concept as you did by stating in your previous comment “It seems logical to me that having an acid taken into the cell will increase it’s acidity”, and now you reached the point where you can back-up that idea with science 🙂

          Kind regards,

  24. “A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin”
    recommended pantoprasole dosage at 240mg intravenous which is valid maximum dose for IV.
    pantoprazole was administered prior to doxorubicin. 2 out of 24 had a partial partial response.
    couldn’t find detailed patient information (whether were these pretreated heavily or not) as no access is available to paper.

    beware of “Cognitive problems of breast cancer survivors on proton pump inhibitors”
    though another report “Proton pump inhibitor prescriptions and breast cancer recurrence: A Danish nationwide prospective cohort study Research year Report”
    done on big cohort doesn’t mention that.

    couple of other trials were done with other drugs (newest) where PPI found ineffective, indeed.

    1. Thank you.
      Omeprasole and even better Lanzoprasole seems to be a better.
      Also, its best to address other proton pups in parallel. (As we know, if important gates are open, tumors will switch to dose and survive.)

      Kind regards,

      1. Hi Daniel

        it might be possible to drug try all pumps for interchemo duration, but co-administration of all that staff with chemo scares me,
        as there is no live data and sometimes no time for small step up-adjustment in case of aggressive tumors.
        do you think playing with biopsy material in-vitro is feasible for such cases? does someone do that so it can be ordered?

        Best Regards


  25. Hello,
    What is your opinion regarding carboplatin and proton pump inhibitor?
    I have read that cisplatin could be a weak acid or a base. However, carboplatin has different chemical composition than cisplatin.
    Whats your point about carboplatin?

    1. Dear Marta,

      Carboplatin and cisplatin are somewhere in a more neutral area. However, there are studies suggesting Omeprazole in high dose could increase effectiveness of Cisplatin and here are reported the results of a clinical trial in triple negative breast cancer where Omeprazole prior to chemo (including Carboplatin) helped increasing the effectiveness of the treatment from somewhere around 40% to about 70%

      So there is a good chance Omeprazole prior to Carboplatin would help.

      Kind regards,

  26. Hello,

    My mum is undergoing chemotherapy (doxorubicin) and bevazicumab. I think ompeprazol is a must. But I wonder if bevazicumab is a weak or acid base. I know that it is a protein, but proteins contain both weakly acidic and weakly basic. I am lost. What is your opinion about omeprazol and bevazicumab?

    1. Hi Marta,

      I searched a little in the literature and there is nothing standing out about Avastin one way or the other. So I would probably focuss on supporting Doxorubicin two ways. 1. focus on lowering the acidity around the tumor; 2. focus on disrupting lysosomes (with e.g. HydroxyChloroquine) to lower the chance Doxo will be sequestrated in the lysosome. Omeprazole can also act on that but it would be best to have HCQ as well in my view. The dose of Omeprazole used in clinical trials to support weak base chemo was relatively high and it has been discussed in another post on this Blog.

      Kind regards,

  27. Hi Daniel,

    I tried to access the PDF where this is explained but the site is not responding so perhaps
    you can help me.

    I am trying to understand how oral Sodium BiCarbonate can alter the pH at the tumor site.
    as I am really skeptical about people taking oral Sodium BiCarbonate to alter the tumor pH
    as it will react your stomach acid. Simple chemistry and to my knowledge unavoidable.

    Really would like to know which pH, the pHe or pHi?
    Perhaps you can explain how this is possible?

    Thanks for all your work, really great website.
    Kind regards

    1. Dear Wim,

      Thank you for your question.

      The discussion, at the point you refer to, was about the external pH.

      The question is very fair, and the answer is complex and challenging from a theoretical point of view. However, in order to search for answers without us being lost in theory, we can look from an experimental point of view and see if we can find experiments indicating the external pH can be manipulated with bicarbonate given orally to animals or humans. The article I mentioned above in the reference is such an article addressing this subject from an experimental point of view. I checked the link and indeed it doesn’t work anymore as the whole website post in it is not there anymore. Fortunately, I could find it here The results are discussed in page 5 of the document (same as page 9 of the PDF).

      Thank you so much for the kind words on the website. There was not much published recently as my main focus now is MCS Formulas as the goal is to put together one of the best food supplements available in the World and that takes a huge amount of work. But as soon as things are set there, I will start publishing again, as there is so much to say and so many new treatment options to discuss.

      Kind regards,

      1. Hi Daniel,

        Thank you so much for taking the time to answer my question.
        I will certainly read the document as I am really interested to learn
        more about the (bio)chemistry (as a physicist).

        I am also looking into the bio-availability of supplements and
        possible synergy vs whole plant based diet
        as promoted by Michael Greger (

        Kind regards

  28. Hi Daniel,

    in this paper they talk about the risk of myopathy with the use loratadine and atorvastatin to inhibit MCT4. And that the muscles are more prone to acidification because they produce a lot of acid lactic specially with physical activity.
    So my question is it dangerous or risky to do sports while taking MCT4 inhibitors and is it the same problem with the other acide efflux inhibitors (CAIX sodium/hydrogen…)?

    Kind regards,

    1. Dear Waka,

      Thank you for the question.

      The answer on short is yes, when the sport is forcing our body to go beyond its normal limits.

      As discussed here fermentation is the way cells in the human body can produce energy when they are deprived of oxygen, but they are still required to be active.

      Cancer cells are often overactive while normal cells not, and this leads to the selectivity of the above strategy.

      However, if we push normal cells to become overactive (such as during intensive sports) while we do not provide them enough oxygen, they will switch to fermentation and produce protons as well that need to be pushed out via. That is the moment when using proton pump inhibitors can lead to important side effects.

      If on the other hand, we perform sport to a level that the body is used with, there will be no extra effort and no need for fermentation – this implies reduced to no side effects.

      All proton pump inhibitors can lead to the same outcome – the more effective they are the higher the anti-cancer effects but also the higher the side effects during intense sports.

      Kind regards,

  29. Thank you for your response.
    What do you think about this protocol for the ph strategy :

    Ellagic acid 800mg
    DHA 1.4g
    Cimetidine 200mg*2

    Acetazolamide 250mg

    Lansoprazole 60mg

    Diclofenac 25mg*2
    Loratadine 10mg*2
    Triphala 2g

    And of course Metformine 1.5g and maybe meclozine 25mg*2

    I am trying to combine some products together for the same target to reduce some drug dosage like diclofenac or cimetidine.
    I still hesitate to take atorvastatin for its side effects, or maybe just 10 or 20mg. Is it worth it?
    Also, Cimetidine is increasing the availability of loratadine, metformine and atorvastatin.
    Do you think it’s enough for a breast tumor of 4*3cm?

    Kind regards,

  30. Dear Daniel,

    I was wondering whether the Wim Hof Method could be of use here. Especially the breath work seems to significantly increase blood ph for several hours ( This and other studies also show that it has strong anti-inflammatory effects (e.g. and improves (or at least changes) the immune function.
    Here you can also find an intersting discussion about the possible effects on cancer:
    In regard to cancer I am very sceptical about the value of the ice baths, but the breathwork seems promising to me. Do you think it might help when following an alcalinization strategy?

    Anyway, thank you for another great article!

    All the best,

    PS: My personal experience with WHM has nothing to do with cancer, but I am sharing it anyway: My whole life I got sick 2-4 times per year, often coughing and sneezing for several weeks. After starting this method I have not been sick for 4 years. Plus, I was never really cold anymore. Before I was always wearing several layers during winter.

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