pH in Cancer & Tumor Acidification: A Top Treatment Strategy

Summary:

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.

Mechanisms:

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:

• http://www.nature.com/nature/journal/v491/n7424/fig_tab/nature11706_F1.html
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826530/figure/F2/

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 https://www.nature.com/articles/cddis2014587
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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264547/

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150086/?page=6 However, on the other hand there are studies showing that Omeprazole, a drug inducing higher extracelular pH can also help 5FU https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101238/ which is puzzling to me and needs to be further clarified
An article discussing this aspect is here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502609/

**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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502609/
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.)

One 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).

Safety:

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.

Source:

Amiloride, Acetazolamide, Statins (drugs on prescription) are available at online pharmacies such as http://www.buy-pharma.co/

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:

• Advanced Medical Therapeutics: http://www.amtcare.com/ph-manipulation-therapy.html

Application on humans:

Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. http://www.ncbi.nlm.nih.gov/pubmed/26297142

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 http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2362.pdf

Synergies:

Chloroquine: Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. http://www.ncbi.nlm.nih.gov/pubmed/24492472

Local Hyperthermia (Ref1, Ref2, Ref3, Ref4)

Radiation

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.” http://www.google.com/patents/EP1713481B1?cl=en

References:

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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826530/

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 (↑pH_i/↓pH_e, 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 pH_i and pH_e 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 http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2362.pdf

Proton pump inhibitors for the treatment of cancer in companion animals. http://www.ncbi.nlm.nih.gov/pubmed/26337905

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. http://www.ncbi.nlm.nih.gov/pubmed/26597250

‘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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756368/

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. http://www.ncbi.nlm.nih.gov/pubmed/22360553

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. http://www.ncbi.nlm.nih.gov/pubmed/21155627

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 http://ff-imt.com/assets/download/publications/extrac_pH_Tumor_response.pdf

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 http://atlasgeneticsoncology.org/Deep/V-ATPaseInCancerID20104.html

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 http://www.ncbi.nlm.nih.gov/pubmed/16724055

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 http://www.nature.com/nature/journal/v491/n7424/full/nature11706.html

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 http://mct.aacrjournals.org/content/1/8/617.long

Melanoma cells in vivo maintain intracellular pH (pH_i) in a viable range despite an extracellular tumor pH (pH_e) 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 pH_i at low pH_e 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 (pH_e) of 7.3, 6.7, or 6.5 in melanoma cells that were grown at pH_e 7.3 or 6.7. The activity of MCT isoform 1 (MCT-1) was up-regulated in three melanoma cell lines at low pH_e, 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 pH_e 6.7 instead of pH_e 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 pH_i. Taken together, the data indicate that MCTs are major determinants of pH regulation in melanoma. In contrast, keratinocytes and melanocytes under low pH_econditions relied on NHE-1. Inhibitors of MCTs thus have great potential to improve the effectiveness of chemotherapeutic drugs that work best at low pH_i, 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 http://www.jpharmsci.org/article/S0022-3549(16)00310-5/pdf

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 http://www.ncbi.nlm.nih.gov/pubmed/14585264

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 https://www.sciencedaily.com/releases/2016/01/160125114243.htm

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 http://cancerres.aacrjournals.org/content/76/6/1381

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. http://www.ncbi.nlm.nih.gov/pubmed/19276390

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 https://www.sciencedaily.com/releases/2016/03/160317114538.htm

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. http://www.ncbi.nlm.nih.gov/pubmed/14585264

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. http://www.ncbi.nlm.nih.gov/pubmed/26152355

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. http://www.ncbi.nlm.nih.gov/pubmed/26755530

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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765265/

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy http://cancerres.aacrjournals.org/content/76/6/1381

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 http://www.mdpi.com/2218-1989/8/1/2/htm

Macrophages and Energy Metabolism in Cancer: The Ketogenic Connection https://www.hormonesmatter.com/macrophages-energy-metabolism-cancer-ketogenic-connection/

Systems analysis of intracellular pH vulnerabilities for cancer therapy  https://www.nature.com/articles/s41467-018-05261-x

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. https://www.ncbi.nlm.nih.gov/pubmed/30101388

Dichloroacetate induced intracellular acidification in glioblastoma: in vivo detection using AACID-CEST MRI at 9.4 Tesla. https://www.ncbi.nlm.nih.gov/pubmed/29143921

In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide. https://www.ncbi.nlm.nih.gov/pubmed/29749579

Topiramate induces acute intracellular acidification in glioblastoma. https://www.ncbi.nlm.nih.gov/pubmed/27613534

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells. https://www.ncbi.nlm.nih.gov/pubmed/28467979

Characterization of the mechanisms by which Carbonic Anhydrase IX facilitates tumour growth and metastasis https://open.library.ubc.ca/cIRcle/collections/ubctheses/24/items/1.0166209#downloadfiles

Therapeutic Targeting of Cancer Stem Cells: Integrating and Exploiting the Acidic Niche https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433943/

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 https://www.ncbi.nlm.nih.gov/pubmed/31098602

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970867/

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 https://www.ncbi.nlm.nih.gov/pubmed/29900055/

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970867/

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 https://www.ncbi.nlm.nih.gov/pubmed/26719539/

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 https://www.ncbi.nlm.nih.gov/pubmed/31395464

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 https://www.hindawi.com/journals/jo/2019/2084195/

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 https://www.ncbi.nlm.nih.gov/pubmed/19276380/

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230683/

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? https://www.medicalnewstoday.com/articles/324767

Other references:

A nice long post on pH: http://www.drjacobsinstitut.de/?RegEnergetik%2FS%C3%A4ure-Basen

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