Glucose Absorption Inhibitors to Inhibit Tumor Growth

Background:

I am writing this post in the context in which multiple readers and contributors to this website have shown interest in the potential of drugs and supplements that have the capability to inhibit glucose absorption in cancer cells. I am glad to see this interest as I also find this subject very relevant and would like to thank Ergin for triggering this subject. I actually discussed this part of this subject more than a year ago, showing the (to me) huge potential of glucose absorption inhibitors such as Phlorizin in cancer treatment as already demonstrated in humans http://www.cancertreatmentsresearch.com/phlorizinphloretin-a-strong-glucose-transport-inhibitor/

As we often discussed on this website, glucose is extremely important for tumors. It represents one of the main energy source and some tumors, when deprived of glucose can die. And if they do not die, at least they will further grow much slower and will be weaker and susceptible to other treatments such as chemo. All these aspects are basic knowledge, so well know that there is no need for reference to support these statements. For example, PET scan works exactly based on the fact that tumors like so much glucose.

If next to inhibiting glucose absorption we can also inhibit mitochondria function in cancer cells, there is an even higher chance that the tumors will be affected. But this subject, related to mitochondria modulation, will be discussed in details elsewhere. For now, here are a few examples of mitochondria inhibitors: Pyrvinium Pamoate, Meclizine, Doxycycline, Metformin (Ref.), Canagliflozin (Ref.) (thanks to Helga for pointing this out), Oligomicin (Ref.). The first five are FDA approved drugs currently used for various illnesses with a clear safety profile.

Glucose absorption:

Going back to glucose absorption, it is known that glucose is transported into the cells via two classes of hexose transporters, namely,

  • the SGLT (sodium-dependent glucose transporter) family and
  • the GLUT (facilitative glucose transporter) family,

and that SGLTs transport glucose against the concentration gradient whereas GLUTs do so along the gradient (Ref.).

SGLT2 has a greater transport capacity and reabsorbs glucose in combination with sodium in the ratio 1:1. SGLT1 has a higher affinity for glucose and reabsorbs glucose in combination with sodium in the ratio 1:2. Note that both transporters are secondarily active owing to their dependence on the activity of the Na+/K+-ATPase for the active removal of sodium (Ref.) Also note that this is a connection point between sodium-based glucose absorption and the cardiac glycosides (such as oleander, bufalin, etc.) which are Na+/K+-ATPase inhibitors and as a result will also lower the function of SGLT1 and SGLT2.

The glucose transporters are very relevant for all the cells, since they represent the doors for the glucose to enter the cells.

Nearly all cancer types have some of these transporters over expressed in order to deal with the short-term high-energy required and develop fast. Because, cancer cells are using most of the glucose in an inefficient way, from the energy production point of view (that is called fermentation or glycolisis), they require large amounts of glucose and thus a large number of glucose transporters on their membrane.

However, it is very important to realize that in normal conditions most cancer cells are over-expressing GLUT transporters (specifically GLUT1) and very little SGLT transporter types. There is a large amount of literature supporting this (Ref.1, Ref.2, Ref.3, Ref.4, etc.). In addition, GLUT1 has been also shown to be very important for the most difficult to treat type of cancer cells population called Cancer Stem Cells (Ref.)

To have a feeling on the over expression of GLUT1 in various cancer cell types here is the protein atlas database showing that: http://www.proteinatlas.org/ENSG00000117394-SLC2A1/cancer

And here is the expression of SGLTs in various cancer cell types:

In line with the above links, indeed, it has been shown that not all the SGLT2 inhibitors can reduce the glucose absorption in cancer cells, as there are multiple types of transporters available on the membrane that can be different for different cell types. For example Canagliflozin, but not Dapagliflozin could decrease glucose uptake in prostate and lung cancer cells and it has been suggested to be a result of the fact that Canaglifozin is also an inhibitor of SGLT1 and possibly GLUT1 (Ref.). Beyond its impact on glucose transporters, Canagliflozin seems to also have an off target action against cancer cells via the activation of AMP-activated protein kinase (AMPK) and as a result decrease mitochondrial respiration.

But things are not that simple …

In contrast to the above suggesting that SGLTs are not that relevant in cancer, there is a relatively recent study making things a bit more complex, as it shows that in some cases SGLT2 inhibitors can actually kill cancer cells such as those of pancreas and prostate via glucose absorption inhibition (Ref.). This is strange since most of the literature indicates that SGLT2 is not that relevant in cancer.

In order to make sense out of that, and unify both “sides” of the research, here is how we could understand it:

  • Glucose absorption via SGLTs requires the right sodium gradient that is “arranged” by the Na/K transporter but that costs energy (ATP).
  • In contrast to that, glucose import via GLUTs does not require energy as it simply depends on the glucose gradient.
  • Typically, when there is enough glucose in the blood, cancer cells will express GLUT1 only, since glucose will flow in the cancer cells without the need for the cell to spend energy
  • However, when there is not enough glucose in the blood the cancer cell has to “start the engine”, over express SGLTs  that require energy in order to extract the little glucose that is available around the tumor cells
  • This is how the scientists also understand the mechanism (Ref.)
  • If the above is true, you could expect that there will be more SGLT over-expression at the center of the tumor (hypoxic area) where there may be less glucose available. Indeed, the hypoxic area is also the one that will be most dependent on glucose since it can not use mitochondria to produce energy due to the lack of oxygen
  • And yes, if I look at the picture of the tumor, Canagliflozin (next to gemcitabine) used in this study lead to an increase necrotic area at the center of the tumor which is typically more resistant to treatments (Ref.)
  • Even more, Dapagliflozin (next to gemcitabine) cause the necrosis in the tumors that were larger, i.e. the higher the tumor, the more necrotic area (Ref.) which I would expect since it does not have impact on GLUT1 as Canagliflozin does, but is very specific to SGLT2 which will only start to be over-expressed when there is no glucose which should be the case even more at the center of large tumors.
  • Based on the above you could argue that we should chose between e.g. Dapagliflozin and Canagliflozin depending on the tumor size and glucose status in the body.
  • Therefore, Dapagliflozin may be more relevant for the very large tumors, while Canagliflozin may be more relevant for smaller tumors in people with high blood glucose levels (e.g. who do not follow a low-sugar diet and do not use other glucose lowering medication).

Glucose absorption inhibitors:

Therefore, inline with the literature, inhibition of glucose transport is a great tool to fight against cancer and also support other treatments such as chemo, radiation, new treatments such as 3BP, Salinomycin, etc. Best is to also combine it with a mitochondrial modulator such as those discussed above, e.g. Metformin.

From an effectiveness point of view, best would probably be to combine GLUT1 + SGLT2 inhibitors. But such combination may be too effective and that could be dangerous to normal cells as well.

This is why, I would focus first on GLUT1 inhibitors since GLUT1 is expressed in normal conditions and since GLUT1 inhibition by Phlorizin has already been shown to be effective in humans (Ref.). Here is a list of such inhibitors:

  • Phlorizin/Phloretin– probably some of the most effective GLUT1 inhibitors I know and already shown to lead to amazing results in humans (Phlorizin is also a SGLT inhibitor). The draw back is that it can only be used IV since the oral absorption is too low. Discussed in details here http://www.cancertreatmentsresearch.com/phlorizinphloretin-a-strong-glucose-transport-inhibitor/
  • Canagliflozin – according to the reference cited above, it also inhibits GLUT1. Fortunately, this drug is available as a tabled under the name Invokana. It has been recently approved for the use in diabetics. Wholesale price of Invokana is $8.77 per tablet, or $263.10 for a one-month supply. Retail pharmacy prices are about $349 to $405. (Ref.) This is a drug from the chategory of gliflozins
  • Verapamil – this is a “heart-drug” available anywhere across the world and cheap, also known for its capabilities to reduce the multi drug resistance of cancer cells and increase chemo effectiveness (Ref.). It has been found to also act as a GLUT1 inhibitor (Ref.)

Other GLUT1 inhibitors, but probably less effective compared to the above are Diclofenac via the inhibition of MYC (Ref.), Fisetin, myricetin, quercetin, apigenin, genistein, cyanidin, daidzein, hesperetin, naringenin, catechin, Graviola (Ref.)

If the patient is on e.g. ketogenic diet or if we can not access one of the GLUT1 inhibitors, we may want to consider a SGLT inhibitor such as:

SGLT2 inhibitors should fit nicely ketogenic diet since SGLTs are probably over-expressed in those patients.

Note: canagliflozin and derivatives has been patented as a treatment of cancer https://www.google.com/patents/WO2016134486A1?cl=en

Conclusion:

When having to deal with cancer, I would strongly consider the IV treatment with Phlorizin or the oral drugs such as Canagliflozin and Dapagliflozin. They could be used:

  • together with chemotherapy or radiotherapy to increase treatment effectiveness
  • together with new treatments such as 3BP, Salinomycin to increase treatment effectiveness
  • together with mitochondria inhibitors such as Metformin

References:

Functional expression of sodium-glucose transporters in cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522748/

Cancers require high amounts of glucose to grow and survive, and dogma is that uptake is facilitated by passive glucose transporters (GLUTs). We have identified a new mechanism to import glucose into pancreatic and prostate cancer cells, namely active glucose transport mediated by sodium-dependent glucose transporters (SGLTs). This means that the specific radioactive imaging probe for SGLTs, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside, may be used along with positron-emission tomography to diagnose and stage pancreatic and prostate cancers, tumors in which the GLUT probe 2-[18F]fluoro-2-deoxy-d-glucose has questionable utility. Moreover, we suggest, based on our results in mouse models, that Food and Drug Administration-approved SGLT2 inhibitors may be used to reduce the viability of pancreatic and prostate cancer cells in patients.

Verapamil inhibits the glucose transport activity of GLUT1 https://www.ncbi.nlm.nih.gov/pubmed/20354917

Calcium channel blocker toxicity has been associated with marked hyperglycemia responsive only to high-dose insulin therapy. The exact mechanism(s) of this induced hyperglycemia has not been clearly delineated. The glucose transporter GLUT1 is expressed in a wide variety of cell types and is largely responsible for a basal level of glucose transport. GLUT1 also is activated by cell stress. The specific purpose of this study was to investigate the effects of the calcium channel blocker verapamil on the glucose uptake activity of GLUT1 in L929 fibroblasts cells. Dose-dependent effects of verapamil on glucose uptake were studied using L929 fibroblast cells with 2-deoxyglucose. Verapamil had a dose-dependent inhibitory effect on both basal and stress-activated transport activity of GLUT1. Basal activity was inhibited 50% by 300 μM verapamil, while 150 μM verapamil completely inhibited the activation induced by the stress of glucose deprivation. These effects were reversible and required verapamil to be present during the stress. Alteration of calcium concentrations by addition of 5 mM CaCl₂ or 4 mM EDTA had no effect on verapamil action. This study reveals the unique finding that verapamil has inhibitory effects on the transport activity of GLUT1 independent of its effects on calcium concentrations. The inhibition of GLUT1 may be one of the contributing factors to the hyperglycemia observed in CCB poisoning.

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respirationhttps://www.ncbi.nlm.nih.gov/pubmed/27689018

These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

GLUT1 as a therapeutic target in hepatocellular carcinomahttps://www.ncbi.nlm.nih.gov/pubmed/19874261

Primary hepatocellular carcinoma (HCC) is one of the most fatal cancers in humans with rising incidence in many regions around the world. Currently, no satisfactory curative pharmacological treatment is available, and the outcome is mostly poor. Recently, we have shown that the glucose transporter GLUT1 is increased in a subset of patients with HCC and functionally affects tumorigenicity. GLUT1 is a rate-limiting transporter for glucose uptake, and its expression correlates with anaerobic glycolysis. This phenomenon is also known as the Warburg effect and recently became of great interest, since it affects not only glucose uptake and utilization but also has an influence on tumorigenic features like metastasis, chemoresistance and escape from immune surveillance. Consistent with this, RNA-interference-mediated inhibition of GLUT1 expression in HCC cells resulted in reduced tumorigenicity. Together, these findings indicate that GLUT1 is a novel and attractive therapeutic target for HCC. This review summarizes our current knowledge on the expression and function of GLUT1 in HCC, available drugs/strategies to inhibit GLUT1 expression or function, and potential side effects of such therapeutic strategies.

GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815417/

Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium‐driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co‐transport.

Attacking the supply wagons to starve cancer cells to death https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833639/

The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

Use of canagliflozin and derivatives thereof in the treatment of cancer https://www.google.com/patents/WO2016134486A1?cl=en

The use of canangliflozin and derivatives thereof in the treatment and prevention of cancer is disclosed. Said compounds have been previously determined to be selective sodium glucose transporter 2 (SGLT2) inhibitors useful in the treatment of diabetes with effects that are similar to metformin. Canagliflozin has now been determined to activate AMP-activated protein kinase (AMPK) and inhibit the growth of a range of cancers. Further to this, use of canagliflozin in combination with other chemotherapeutics has now been determined to give rise to increased anti-cancer activity.

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic micehttps://www.ncbi.nlm.nih.gov/pubmed/28430653

Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.

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138 thoughts on “Glucose Absorption Inhibitors to Inhibit Tumor Growth

  1. THANK YOU!
    I must understand it:) ,again there was a big silence.You were working on this very valuable subject.
    I have to say thanks to you for Humanity.

    1. Thank you too Meech. How are you? How is the new chemo treatment going? Have you already started that? Yes, Metformin seems to be so suitable that I was reading somewhere it is part of >150 clinical studies.

      1. Oh wow, guess the medical industry is catching up.

        I’m good, still feeling well. Chemo started two Wednesdays ago, and I have the chemo infusion again this Wednesday for my second cycle.

        It’s tough to say how it’s going; the two tumours I can feel (supraclavicular at about 1.5cm, external iliac lymph node at about 6.5cm – the tumour blocking the ureter) don’t feel like they’ve gotten smaller. I was having hematuria into my nephrostomy tube with pain at the site where the tumour blocks the ureter for about 7 days straight prior to chemo, which was abnormal. This resolved one painful, night, 2 days after chemo, where I started getting even more pain and pressure around the tumour site, along with urinary discharge at the tube site. The following morning, the urine was clear for the first time in 9 days.

        I had some chest pain and coughing that came on very acutely three days before chemo, and has since disappeared.

        Very tough to say whether this was all unrelated phenomena or whether the chemo has had any effect.

        My blood counts did fall below the normal threshold but only slightly, as the calculations for carbo weren’t done the greatest since they were done based on bloodwork, as opposed to their usual of doing it based on a 24 hour urine analysis. Hopefully this week they fall a bit less. Had some nausea and upset stomach for a few days. I only took ondansetron the day of chemo, so it wasn’t too bad.

        I’m currently only taking vitamin D, Metformin, DCA, Omega 3 oil, Shark liver oil, and a probiotic along with the chemo. All of them concurrently, apart from DCA, which I’m taking at a lower dosage than usual on my off-weeks, just to try to minimize the platinum+DCA synergistic neuropathy.

        1. Thank you Meech. Great to hear you are feeling well! I hope the treatment of this Wednesday went well as well. What is the time frame in which the clinic expects response from this strategy you are currently trying? Kind regards, Daniel

          1. Thanks Daniel!

            I think they expect it quite quickly. The idea that they tell me is that it’s “cancer-immunotherapy”, because there’s a sufficient dose to kill cancer cells, while also keeping the blood cells from dying off too much so that the immune system can participate after the initial cell death. He said there’s been responders within a few days. Also, they said they’ve been having great results by combining it with local hyperthermia, and have been referring patients to a separate clinic. So I did an hour session of that today. Hoping for some results soon.

            1. Very good idea with hyperthermia. Indeed I know clinics in Germany are seeing good results when they combine chemo with hyperthermia local and whole body. By combining I mean using hyperthermia after at about 24h. I hope you will see very good results, Meech!

              1. Thanks Daniel.

                It’ll be difficult seeing results apparently since it is a form of immunotherapy, and on scans, immunotherapies can do a whole wide range of things from showing decrease in tumour size, showing stability with late response, or showing actual growth and increase in metastatic lesions, prior to a decrease. And these three possibilities are only when there is an actual response to the therapy.

                The Medicor site looks like they’re about to publish reports of their patients during SEF Chemo, and have published one case report of an external tumour of the breast which had a great response (graphic photos obviously). So if you’re interested, it may be something to keep an eye out for.

                  1. Dr. Khan has claimed that the SEF Chemo is a form of immunotherapy and that they’ve seen the same patterns with scans as would be seen with immunotherapy.

                    The hyperthermia location also told me that the hyperthermia is a form of immunotherapy and that they generally avoid scans for at least 14 days after the completion of a session due to potential false positives.

                    1. Hi Meech, thank you for the explanation. Now, I understand why they are relating them as it is easier to explain to the people, but the reality is that they are totally different mechanisms. Chemo or hyperthermia are not directly modulating the immune system, to my knowledge. Indirectly, yes. But I can imagine that nearly all effective treatments (also like 3BP) may show (but not necessary) first a “growth” that could be related to the inflammatory events that are triggered when cancer cells are killed. This is why I would combine any effective treatment with anti inflammatory medication, in line with the very valuable video you recently shared.

                    2. Btw, you may want to mention to Dr. Khan that we are discussing your positive experience on this website, accessed by many, so that he adds extra attention to your treatments. That will be good for you and him at the same time. And off-course for many of us here that care about you, at least myself.

                    3. Hi Meech

                      I’m reading a lot about SEF Chemo , its very interesting

                      I wish to hear all the best and positive response about it soon 🙂

        1. As I know, in Romania, if the customer smiles to the pharmacist explaining how much he needs it, the pharmacist will give it without prescription. They are more flexible and the strong competition between the pharmacies helps as well. There are so many pharmacies, maybe one every several hundred meters in the large cities. As a bonus, there are many Hungarian speaking people and probably pharmacist that could be contacted by internet by anyone from Hungary. This world is full of options … 🙂

          1. Eheh.. the smiling strategy in the pharmacy would be very alien here, if the state puts prescription on distilled water they will NEVER sell you distilled water. Next Time i am in Romania i buy Beers and drugs. Happy 2017.

        2. I know 100% that some of the ex-Yugoslavia nations will be similar to Romania in terms of prescription accessibility, if they’re more accessible. If you’ve got the money to pay for it, it shouldn’t be too much of an issue.

  2. Dear Daniel,
    thank you for a great post.
    I have read that cancer cells can survive glucose deprivation by switching to glutamine and even other sources. Do you have any opinions on this?
    Regards Ernest.

    1. Hi Ernest,

      You are right. Tumors may switch on other fuels but all the others will require mitochondria to produce energy. This is why I mentioned above about the idea to combine glucose absorption inhibitors with mitochondria inhibitors such as Metformin, Meclizine, etc. Actually, and fortunately, Canagliflozin is such a mito inhibitor at the same time with its glucose absorption inhibition.
      Is this answering your question?

      Kind regards,
      Daniel

      1. Hi Daniel,
        Yes I think it does. I missed that point on first reading.
        There is a lot to digest so I will give it more consideration.
        Thanks a lot.
        Warm regards,
        Ernest.

  3. http://www.wjgnet.com/2220-6132/full/v3/i2/37.htm
    I like glucose absorption inhibitors too much.
    Especially the combinations with glycolitic inhibitors.And metformin is must in any treatment,for my thoughts.
    There are lots of things to talk about them.
    Please look at the links.
    I am sure when people know what to search,evrything will be more clear.
    I didnt know how many GLUT and SGLT and their importance in treatments.
    https://www.google.ch/patents/US20140142056

    1. Dear Daniel,
      If you can find time please look at the 1st link.
      I am sure you know nearly all drugs in the link but ,you ll like it.
      I will write the other news tomorrow,i am on the way coming from chemo.
      We have to talk with our new member Hectoria
      also
      Kind Regards
      Ergin

      1. HI Ergin,

        Thanks I will respond this evening when I am at home.

        Also, when you find time can you please share here (on the post dedicated to you) what was the origin of your mom’s strong reaction to chemo treatments you experienced during the past month and how you now succeeded to avoid it?
        I think it will be useful for others that may encounter the same.

        Kind regards,
        Daniel

      2. Hi Ergin,

        As promised:

        Thanks for the link http://www.wjgnet.com/2220-6132/full/v3/i2/37.htm It includes a good list of accessible Glut 1 to 4 inhibitors. The drawback is that most of the accessible ones are also not bio-available so you need IV solution such as the one discussed previously, i.e. Phlorizin.
        It would be good if we find such list with inhibitors of others GLUTs from GLUT5 to GLUT 14.

        GLUTs are also nicely discussed here: https://www.hindawi.com/journals/ije/2010/205357/

        Now, the questions is what can we do if there are so many GLUTs and since they are differently expressed in different cancers?

        Well, first I would take this as a rule: GLUT1 is expressed in most of the cancers. So Phlorizin may often work.

        Second, I would check each glut, from 1 to 15 or so, using this database http://www.proteinatlas.org/ENSG00000197496-SLC2A10/cancer
        Assuming that the cancer of interest is shown in the list of the database, we can see what is typically in terms of relevant GLUTs in the cancer we are interested in. So we can conclude that for cancer xxxxx, GLUTx GLUTy GLUTz are the most relevant as are most over expressed and need to be inhibited. Next, I would search for inhibitors for these specific GLUTs in articles such as this one http://www.wjgnet.com/2220-6132/full/v3/i2/37.htm

        Another option is: we can also conclude that it is too much to do all this and only consider the methods discussed in the post above.

        Yet another options is: since GLUTs are functioning based on glucose gradient, we can focus on lowering blood glucose with ketogenic diet, metformin etc. In that case, we end up with SGLT over expression that can be addressed with the drugs discussed in the post above

        A different option, which is the chosen option of a doctors I was discussing with these days, is to actually let the Glucose transporters functioning and make use of them, by pushing 2DG through them together with other (serious) glycolisis inhibitors. Btw, as a side point, note that Vit C enters the cells via glucose transporters.

        Kind regards,
        Daniel

        1. Dear Daniel,
          I wrote a message but it is lost because i didnt logged in.If you find it could you please erase it.I am writing again.

          These days i feel that i learned nothing about cancer metabolism.It is really interesting after entering inside the subject.
          Resistant cells and sensitive cells are very different.We have to fight with different drugs.
          I didnt find time for searching too much but i am sure we will search alltogether.
          This is my latest finding:
          http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(20010901)92:5%3C1144::AID-CNCR1432%3E3.0.CO;2-T/full
          The ovarian cancer patients who has GLUT1 positive cancer(more agressive and takes more glucose inside by GLUT1)responds to chemo better than the others.And lots of complete responces in first line chemo.
          But later when reccurence comes,they live shorter than the negative GLUT1 cancers.Nearly x2.
          And a question come into my mind which always eats my brain.
          Glucose helps in the first line chemo:
          When there is too much glucose,there is too much MG(METHYGLYOXAL).
          And it helps chemo,we now a paper if it is true.Diabetic patients responds chemo better than the non -diabetics.And metformin reduces MG in blood.But at last, diabetic ca patients live shorter.Glucose beats MG at last maybe or cancer became resistant to MG.

          When cancer became resistant we have to use GLUT inhibitors or metformin or others,it is clear for me.Because they live x2 more.

          Daniel what is MG?I know your post and read but it is not only used for cancer patients,i read some papers and they are about diabetic researchings not cancer.
          There is stg very special with MG.And i believe there is a very big correlation between cancer metabolism and MG.

          Kind Regards
          Ergin

          1. Hi Ergin,

            That is normal: the more we know the less we feel we know. But the reality is that we know much more 😉
            Can you please share again the article because the link doesn’t work.

            Kind regards,
            Daniel

              1. Thanks Ergin,

                I was looking for this: “Two to 3 weeks after surgery, all patients were submitted to 4–6 cycles of cisplatin-based chemotherapy. Fifty (56%) and 39 (44%) patients received platinum-cyclophosphamide and platinum-paclitaxel combined therapy, respectively.” Ref.

                The higher response to chemo by GLUT1 expressing tumors was connected by the authors with teh agressivness of the tumors expressing these transporters which in turn would fit better chemos that are fighting fast deviding cells.

                However, there is another possibility: as discussed elsewhere https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/ chemos that are weak acids will be better absorbed when the environment around the tumors is acidic. The chemos they used here were actually two that would not depend much on the pH around the tumors (Taxol https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230683/ and Platinum-based) and one very dependent and that would be better absorbed by the cancer cells in acidic environment which is cyclophosphamide https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/

                Therefore, here is how I see the flow: GLUT1 high means also MCT4 high required to export protons and that in turn means pHe low, which finally means higher absorption of cyclophosphamide used here and higher effectiveness as indicated by the study.

                Kind regards,
                Daniel

  4. D-glucose is taken up by Glut1, quercetin also uses it.

    “The flavonone, quercetin, is transported via GLUT4. Quercetin influx into GLUT4 is inhibited by high glucose or cytochalasin B concentrations (7). Conversely, quercetin inhibits glucose and ascorbate transport via GLUT1, -2, -3, and -4”

    “Another explanation for sugar transport asymmetry is that glucose accumulates in an endofacial compartment or vestibule. This promotes futile transport cycling, or recycling, that both lowers the maximal net influx rate and reduces the apparent Km for net glucose uptake” If only there were some futile cycling at the early stages of glucose handling! If there were some way of costing the cell 2 more ATP per glucose then the cancer cell would gain ZERO energy benefit from glycolysis. So if it were to cost 2 ATP to move through Glut1. Also of note is that Glut1 seems to be stuck with D-glucose. Perhaps a medical diet could be used such that d-Glucose would be limited.

    “A high glucose concentration binding in the vestibule widens the vestibular exit to the cytosol, whereas ATP binding restricts it, thereby altering glucose mobility between the vestibule and cytoplasmic compartment.” Wonder if in cancer the ATP binding gate is lost, allowing in more glucose.

    https://www.ncbi.nlm.nih.gov/pubmed/16407180

    1. Dear J,
      Could you please open a little bit this subject.
      I am sorry but I am always using dictionary to understand your language.Too complex for me
      Ofcourse you dont write these valuable findings for me and someone who is scientist can understand.
      But i am wondering what is going on in your messages:)
      In summary is inhibiting GLUT good or not?
      Kind Regards
      Ergin

      1. Erg, don’t get down on yourself!

        I really hope any fancy words that I might have used has not made you feel inadequate: with cancer we are all inadequate. I am highly motivated to do whatever I can to help you and others that are struggling with cancer. We all need to learn and grow together on this oncology journey.

        In all of human history, metastatic cancer has been understood to be completely incurable, though now we are starting to see daylight! It is so difficult for cancer patients to know what to do when they encounter this mountain of research. Sites like D’s can help narrow down the discussion.

        1. Glut1 transporters are a main entry pathway of glucose into cancer cells. D has posted a very interesting article about phloretin as a way to block this mode of entry. I am excited also about his comment that SGLT transporters actually need ATP in order to work, while GLUT1 does not. My idea is if one were to avoid d-Glucose which is used by Glut1, then glucose fed to SGLT could deplete the cell’s energy supply. On first glance I would not see any toxicity issues with this.

          How much ATP does SGLT need to transport 1 glucose molecule?

          1. Erg, this one is interesting.

            Reducing glucose or using ketogenesis might not be enough because the body has given itself a wide safety margin
            to protect itself from a low energy state.

            However, the below article talks about a maximum tolerated approach to glucose reduction.
            They are suggesting that a glucose level close to zero is possible and could have substantial anti-cancer effects, though it would need to be done in an ICU.

            The idea in the article could induce a cancer cure perhaps almost immediately. Without glucose, I am very sure what would be left of cancer. It would be very interesting for this question to be answered.

            Yet, one might try a slimmed down version of their idea without needing an ICU.
            Probably be best to do this in a medical setting, though a more moderate glucose lowering strategy
            would reduce safety concerns. For example, take two weeks to move into ketosis and then move down glucose with MB07803 or others.

            The article gives examples in which those who have fasted or underwent extreme starvation had glucose levels
            of less than 40 mg/dL, another with stable 30 mg/dL, others with obesity who went as low as 9 mg/dL. None of these people had any symptoms. A normal glucose level would be more in the 80-90 mg/dL range. Low glucose normally induces coma. This can happen with glucose levels as high as 40-9 mg/dL. Keto-adaptation appears to prevent this.

            https://www.ncbi.nlm.nih.gov/pubmed/?term=25579853

            1. Thank you J for this very valuable link.Do you have full article?
              I wonder did they use any SGLT inhibitors or not.
              With phlorizin,they say that hypogylicemia does not occur.And no coma in articles.
              I have an idea of using oral dapagliflozin with ketogenic diet for weeks.Than a golden shot of iv phlorizin with fasting.
              What do you think?
              Kind Regards
              Ergin

              1. Thank you for picking up on this one, Erg!
                I am recycling it from the compass thread from a year or two ago.
                I think this is a very good one.
                I am not sure, how does one search for an article on sci-hub?

                Erg, this one was from Medical Hypotheses.
                This isn’t so much a clinical trial as a description of what might be possible.
                They conclude with “further research is needed”.

                The article notes that cancer patients typically are concerned about weight loss so the protocol that they
                suggest actually should not result in any loss of weight. They are able to mimic the effects of fasting using the KD. I would think it would be best not to try and be all that creative with this. Combining fasting and a glucose lowering agent could be dangerous, so I would go with a known and tried route that has achieved this.

                We all are pretty much on side with the concept of bringing down glycolysis as a valid anti-cancer approach,
                though most of the time you really can’t get a good hit at it. Ketogenesis might only give you a modest effect.
                What this article is talking about is a truly radical reduction in glucose. The article explains how it might be possible to move glucose down close to zero. This would almost certainly have a rapid and dramatic anti-cancer effect. However, they note that this is only on the back of the envelope basis and safety concerns would need to be considered and managed perhaps in an ICU context.

                Even still the basic concept still stands.
                Move to ketosis over a 2 week period and then use something to bring down glucose from there.
                They note that there have been various examples in which during starvation etc. people have exhibited astonishingly low levels of glucose without any symptoms. The great part of all of this is that you derive all of these benefits without having to starve yourself months on end. It almost seems too good to be true.

                My best guess would be that any combinations would need to be very carefully considered. Doubling up with phlorizin etc. could be very dangerous. The glucose levels might already be near the minimum possible, further reduction could be dangerous. Probably best to see how such a treatment worked alone. The article does go on to suggest perhaps combining with chemo or radiation. These combos probably would not push on glucose metabolism and perhaps would be safe.

                Yet, overall this one seems like a very good plan. Probably would not want to push it as far as the article goes, though it is surprising how low other trials have gotten without trying anything excessive.

                The methods suggested in the article are not in any way outrageous. For example, they suggest to start off with a 4:1 KD for more than 14 days.

                In this study quoted they starved obese people for 45-60 days. This meant they were keto-adapted.
                Thus, they would not go into diabetic coma with insulin treatment. When the insulin was administered
                their glucose levels declined to 9 mg/dL within the hour “without acute hypoglycemic symptoms”.
                Resistance to symptomatic insulin reactions after fasting 1972; 51(10):2757-62.

                Erg, this is quite startling. Bringing down glucose that much should have anti-cancer effects. I would love to hear from others on the thread on their thoughts. If I could figure out how to start a topic on the forum I think it would be great to carry on the conversation there.

                I do not want to say much about ketosis because I think there are some experts on thread and I don’t want to get it wrong, though ketosis itself does not appear to result in greatly reduced glucose levels. However, using the protocol suggested in the article could massively reduce glucose levels. It is not entirely clear how effective this would be as a cancer treatment, though considering how much cancer cells can depend upon glucose it surely does not seem like a bad start. I think studies have even found that by moving around glucose in the normal range of say 80-100 mg/dL they already start seeing hints of anti-cancer activity.

                Seems like a fairly easy idea to try, though would want to stay within the lines.
                It is possible that within a cancer context, low glucose levels might be more dangerous than even for those with obesity.

                In terms of how they suggested to move down glucose levels, they mentioned insulin and then decided against it, mentioned metformin and had reasons not to use that one, and then they suggested CS-917/MB07803 which were both only in clinical trials. I see no mention of SGLT inhibitors. Yet, they said that all of this was very provisional and more pre-clinical studies would need to be done.

                1. Erg, sometimes on these forums you have to throw an idea around a few times before it clicks with someone. Thanks for picking up on this one. It seems like an easy one and it could be helpful for a broad range of patients.

                  From my reading of this, it makes a great deal of sense. This might actually be mimicing the approach used in other cancer treatments where people basically go on a cancer starving diet. The idea here is that you can have these benefits without the starvation part.

                  Some people might make it to ketosis without reaping the full benefits of low glucose levels. Some of what I saw online said that people in ketosis might bring their glucose levels down maybe to 60 mg/dL from perhaps 80. that is not a great reduction. Yet, a KD with glucose lowering medications one could move into very reduced levels of glucose. From the sounds of things one could perhaps maintain low glucose levels for quite a period of time without symptoms. Some of these people who underwent long term starvation maintained this state for months on end.

                  The article had more of a focus on an immediate near total stop of glycolysis over perhaps a short time frame. One might instead want to think of a more prolonged timeframe while still reducing glucose metabolism substantially. It would be a great one to try out in a clinic context in order to become comfortable and familiar with it. One might do the 14 KD induction and then perhaps go to a clinic for a week while they brought down your glucose in a controlled setting.

                  1. Erg, I am really liking this one, though it really would be best to let the pros run with it.
                    I mean that is why they went to medical school isn’t it?

                    Do you think the Turkish clinic might do this one on the side?

            2. By coincidence, I was looking a few days ago over some of the blood results of my dear wife and she was for very long time at around 45 to 50 mg/dL. It is the same time we were using a lot of natural supplements, including Berberine and others. I would have to check what exactly but things were going very well at that time.
              The diet was simply a vegan one in general + Budwig

              1. Dear D, I was looking at Figure 18.1 (right at the end) of
                https://www.amazon.ca/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920#reader_0470584920

                (Thanks for helping me log into the forum! I want to help the people, though I needed that password to do so.)

                They moved glucose down from about 8 mM to 3 mM in the mice.
                From what I understand of this Figure this stabilized the cancer growth?
                Reducing glucose by a factor of 2 or 3 might be what could occur using a ketotic approach.

                The article that I linked was talking about moving down glucose even more than that. In obese subjects glucose was reduced to 9 mg/dL. This would be about a 10 fold reduction. By looking at the figure noted above, such a large reduction in glucose probably would have a significant influence on the tumor.

                Glad Erg mentioned IPT. The article I linked found no side effects even when glucose levels that were very low in obese people and those undergoing starvation. However, they were fully keto-adapted. If one were to inject insulin into someone who was not keto-adapted then side effects would occur. Article talked of how people with glucose even in the 40-49 mg/dL range could go into diabetic coma if they were not keto-adapted.

                1. Interesting that this article talks of the ketogenic effect with caloric restriction having an anti-tumor effect, then suggests including metformin.

                  It also notes “the most impressive anti-tumor effect … regarding the inhibition of glycolysis came from experiments using 3-bromopyruvate … This process is so fast that there is a concern about the toxicity induced by the necrotic tumor tissue … 3-Bromopyruvate stops both glycolysis and gluconeogenesis …”

                  https://www.ncbi.nlm.nih.gov/pubmed/21530093

                2. Thank J, and imagine what could have happened with an addition of a SLGT inhibitor which I expect wold perfectly fit with ketogenic diet. Maybe someone can write a patent on this 😀

                  You are very welcome with the account, and thank you for contributing – off course I already know you J as you are helping people for so long time, which I very much appreciate. I also appreciate your unique never ending and constant energy during all these years. It reminds me of the running Bunny from the Duracell advertisements 🙂 https://www.youtube.com/watch?v=kaF6FxmixJk&list=PLOC1OsDa8c2r5aTfTHxwoNXi56a0hBJnq or this one https://www.youtube.com/watch?v=dSkgIrmuofY

                  1. ”Because the mechanism of SGLT2 inhibition is independent of insulin secretion and sensitivity, these agents can be combined with other antidiabetic agents.”

                    And there is very little possibility of getting into hypoglycemia with SGLT inhibitors if i true understand.

                  2. D, I am somewhat worried about using combos with the maximal glucose reduction strategy. Bringing down glucose down massively and then combining with something else might result in dangerously low glucose levels. I think the levels noted in the article related to starvation should have substantial anti-cancer effects. Has this ever been done before with cancer? It seems like too good an idea not to have tried. This is exactly what we have been talking about for all these years and here is a method to actually see what happens. Until we have a better understanding of its safety it would be best if it were done in a medical type setting.

                    Funny about the bunny D! I like to think that I am like the boundless energy of the bunny and the cancer can be defeated by depleting its energy with substances such as 3-BP etc. .

                    1. Dear J,
                      I am thinking just opposite of your thoughts about combinations.
                      Brain,liver doesnt express SGLT so there is no danger of hypoglycemia.This should be our novel drug because cancer expresses SGLT.And it looks safe.
                      But maybe dosage is not enough for totally inhibit glucose entry into tumors.Then we should use metformin low dose if we can not make SGLT inhibitors dosage higher.
                      Controlling blood count is not a hard thing,a simple device.
                      But KD is must because of the article,brain uses ketones if there is no glucose.
                      My mother get nearly into coma while IPT,and she was on a hard ketogenic diet.(30mg/dL)
                      But they gave insulin very fast in 25 min.May be KD saved her life.

                      Kind Regards
                      Ergin

                    2. I am glad to hear you liked the bunny link J 🙂 That is how we need to be in this field: maintain energy, perseverance and focus.

              2. D, remember that quote from the compass “an apparent absence of mitochondria” PMID: 25569102 I think that was with respect to renal cancer which makes “Renal cancer has one of the highest incidents of spontaneous
                remission of cancer and it mostly occurs after nephrectomy with pulmonary metastases” from the above article not that surprising to me. Article is suggesting that hypoxia or hypoglycemia would act as a block to tumor growth.

                Also from the article just noted “A low dose of a synthetic glucosteroid (Prednisone or Dexamethasone) plus a low dose of a synthetic progestrone (Provera) at a specific point (Least tumor growth) might free the immune system and allow immunity to develop. It appears that a life saving treatment for untreatable cancer is at hand and lives could be saved.” [that was from an article dated December 2010].

                1. Hi J, I do remember very well our discussion on that subject indeed. And your point is very relevant since those cancer cells with the low amount of mito or no mito should be the most sensitive such such glycolisis inhibition. There were some professors suggesting that cancer cells responding to DCA may not respond in time due to loss of mito (due to increased alkalinity of the intra cellular space). Those should also be sensitive to glyco inhibition if they indeed lost their mitos.

  5. Dear Daniel,
    Have you heard about oxamate and phenformin?
    May be better than DCA+Metformin
    2014 Article.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897486/
    Our results suggest that phenformin has higher cytotoxicity and growth suppression towards cancer cells than metformin. Moreover, addition of oxamate not only reduces lactic acid production but also enhances the anti-cancer effect of phenformin. Our data suggest that this synergistic anti-cancer activity involves simultaneous inhibition of complex I and LDH by phenformin and oxamate, respectively.

    Kind Regards
    Ergin

    1. Hi Ergin,

      Indeed they are well known and researched. Phenformin seems to be indeed more effective but to my knowledge in most of the countries is not available. May still be available as a capsule in China. Otherwise only at chemical suppliers. Is it available in Turkey?

      Kind regards,
      Daniel

      1. Dear Daniel,
        I am thinking that my mission is completed in this website.
        From now on i stopped searching for cancer drugs.
        I feel that i am not helpfull for people.
        I am just waisting your valuable time.

        I am not a scientist nor a doctor but only an engineer trying to understand what the cancer is.
        After reading again my searchings and questions to you,i feel not ok,just waisting your very valuable time.
        Please try to understand me.You have already teach me very valuable treatments.
        I am trying T4 depletion strategy and i hope this will help millions at the end.
        And in 2-3 weeks i will try phlorizin with hyperthermia+low dose chemo together.

        This is enough for me.I will not go to any other treatments that no one understands and too complex as you see.And it will no help for anybody.

        This will be my future strategy for people and for my mother.
        I am always near you.
        Kind Regards
        Ergin

        1. maybe DCA will help your mother now with T4 and glucose absorbtion inhibition.
          I am thinking this may also help my mother
          DCA, Lansoprazole, Metformin, Diclofenac, Simvastatin, T4 Depletion, Glucose absorption inhibition.
          I don’t know if the budwig mixture or hca would be a good addition, or germanium or even vinegar.
          Wishing a nice weekend.
          Alex

          1. Thank you very much Alex,
            I have to focus on phlorizin + hyperthermia without thinking anything.
            I stopped for searching other drugs or combinations.
            This is my duty during coming weeks.Daniel helped me too much from the other side of the world.
            So i have to help people with his findings.Especially phlorizin and T4 strategy.
            But i will need help how to give it iv,how to control blood glucose etc.
            Kind Regards
            Ergin

            1. Hi Ergin!
              Do not go away! For us, not scientists, it is good to communicate in language that we understand. To understand one scientific paper or strategy for me sometimes takes days, as I need to google things that I do not understand.
              Your experience with different strategies is valuable.
              Thanks,
              ieva

              1. Hi Ieva,

                if you search for hyperthermia the site, using the magnifier icon in the top right of the page, you’ll see all the discussions about hyperthermia. There is local and whole-body hyperthermia, carried out at medical-like facilities but you can try some home-based solutions as well, especially if the tumor is close to the surface. We used hot salt for such purpose.

                Best,
                Helga

                1. Thanks, Helga!
                  How much degrees do You get with hyperthermia?
                  I have heard that there is hyperthermia clinic in Russia`s city Novosibirsk – they warm up whole body till 43 degree celsius under general anesthesia. And they notice that less than 43 degrees can make tumor to progress.

                    1. The price in Turkey is nearly 150 usd for 1 hour.
                      They use local hyperthermia in the world for only drug flow into tumors.
                      They dont kill tumors or dont kill enough tumors.
                      You must reach more than 48 degrees to kill them but it also damages normal cells.
                      Thats why we talk about phlorizin + hyperthermia.
                      Phlorizin does stg special to cancer so it is killed on 43 degrees.

                    1. Hi W,
                      Unfortunately there is no place in the world that use phlorizin with hyperthermia that i know.
                      You can ask there is a patent and lots of real cases why noone uses it,but the doctors passed away.
                      May be Daniel knows a clinic who uses it.

                    2. I agree, no official place doing this. Nothing that I can share for now. But I am sure if we search deep enough we will find some doctors doing it or at least willing to start it.

                    1. Hi Daniel,
                      About whole body hyperthermia I would agree that it can be dangerous. I haven`t read much about that procedure. Just in my mind stayed information about 43 degrees as I always wondered can I or can not to go to saunas :)…. as I loved that very much. But now i better to stay away from regular saunas.

        2. Hi Ergin,

          Thanks for sharing your thoughts. I very much appreciate your contribution and hope you will further contribute with both questions but also your new findings. You should be aware of that and not forget that, even if from time to time, it is the human nature of the responsible people to question our actions and reflect on that. When doing that, we need reference points and feedback from others. This is my feedback: Your contribution is very valuable and helped all of us to learn more, including myself.

          Regardless of whether we are medical doctors, scientists, engineers, artists or any other profession, we all have our own value to add as we see life from different perspectives. Cancer was for long time the challenge of this world and still is. That means we need to bring new perspective on this challenge if we want to solve it.

          The answer to cancer is there, there is no question about that. And based on my experience, the answer to complex challenges is simple. We just need to zoom out and see it. But off course we also need some knowledge and that is what we are doing here. Exploring the knowledge and connecting the dots. And I think and feel we are on the right path.

          Off course, in this field, since we are fighting with time, we need from time to time to stop searching and start applying what we learned. When applying, it is essential that we fully believe and expect the intended result. So I am happy that you found the areas you fully believe in and that you can apply them. I am also happy that you have a doctor that supports you with that.

          You are off course not wasting my time. It is those like you that make my time valuable. What could we do better with our time on this planet compared to helping those who need the help and who are actually making use of that help? So please continue doing that, but I agree: discussions on forums take time and this time is very valuable for you as you also need to focus on applying your knowledge. So if you will decide to interact less on this website, I very much understand and even support that. I also had such moments when I realized I should slow down with interaction around the world and focus on my wife’s treatments.

          Finally, your comments are always most welcome and if you decide to slow down at least please keep us up to date with how are things on your side and with the implementation of T4-depletion strategy and Phlorizin at the clinic in Turkey.
          If there are questions, I will always do my best to help. All the best to you and your dear mom!

          Kind regards,
          Daniel

          1. Dear Daniel,
            Thank you very very much for your kind mail.
            I have problems with myself,i have to work on phlorizin but still trying to go to other searches.
            Time is going and still on chemo,i forgut how many chemos really.More than 40?I cannot count.
            We have a very good chance with phlorizin.
            You told me about it 4 months ago.But as you see i am still on searching phase.That makes me to feel stupid.
            If you were me,you began all treaments 4 months ago.
            Still trying to find an alternative to phlorizin,sal,3BP and there is no need for now,maybe after using them and no responce.I have urgently begin phlorizin iv because i believe it more than every treatments.
            Of course i will be in this site forever to help people and maybe ourselves in the future(who knows).
            Thank you very much for your kind mail.
            When i have news about T4 depletion strategy,i will directly write here.

            Kind Regards
            Ergin

        3. hey Ergin
          i highly appreciate your enthusiasm. Even if you are an engineer you might have great ideas in another field. Sometimes its an advantage to be out-of-field. Keep up your spirit, man.

          1. Thank you very much W,
            I have very different projects about PDT ,PTT and electric fields.When my mother will be ok i will begin lab tests.
            I am in communication with some scientists around the world.
            But the time is to begin the treatments what we have in our hand,which Daniel found ,experienced and gave us as a present and freely.
            I really doesnt understand how he found those very valuable treatments.
            Kind Regards
            Ergin

        4. Erg, you mentioned above about a hard KD diet and insulin bringing glucose down to 30 mg/dL and this having serious side effects. The article that I cited above noted that in starving people they have been able to greatly reduce glucose levels without symptoms. I am very interested in learning about the experience that you mentioned. How long had the KD diet been in effect? The article suggested that a minimum treatment period of 2 weeks + would be needed for the induction phase of their proposed therapy.

          I am very excited about this idea and I will be very interested to hear any comments that you might have.

  6. Hi Ergin,

    I also read your comments regularly and they are quite insightful, plus you have a good sense of humor. People learned about phlorizin from you, plus T4 depletion (or who suggested it first? but it is beside the point, anyway). I hope you keep posting!

    Kind regards,
    Helga

    1. Hi Our Dear Helga,
      I am totally misunderstood or i cannot tell it easily because of my language.
      I dont go anywhere,The time is to begin phlorizin by friends here and Daniel’s kind helps.
      People dont need my new findings,they need to hear feedback from T4 strategy and phlorizin which Daniel find and teach me.
      Kind Regards
      Ergin

      1. Hi guys, I would be interested in what your thoughts are on my experience with fasting. Last year I ate no solid food for about 25 days, just green tea and some miso in hot water. I rapidly lost 14 lbs in the first 10 days, but my blood sugar was never really that low. After 10 days, despite no food and no calories, my weight remained stable, even putting on a few pounds, and my blood sugar was totally normal. I was consuming no more than 30 calories a day in the form of miso. I stopped the fast, because I was doing it to starve my tumours, but I realised it was having no effect at all. I felt perfectly normal but tests showed I was low in potassium. My doctor was totally perplexed. Weird huh?

        1. Hi Hectoria.

          I think we should make a forum topic for this.
          For whatever reason I have been unable to make to the forum, though perhaps you could start without me.
          I am hoping D will feel some pity for me and just email me my password.

          We could talk through the idea of “starving the cancer”.
          The article that I quoted to Erg goes into the different stages of starvation. In their staging it takes more than 14 days to achieve Stage 5 starvation. Yet as I noted above it really isn’t necessary to starve for this effect.
          The article talked about using a 4:1 KD diet and then using glucose lowering drugs.
          In different patient groups they have been able to dramatically reduce glucose levels without symptoms.
          I am not sure whether this has ever been done in cancer patients before, though there seems to be substantial potential
          for anti-cancer effects. Glucose does tend to feed the cancer and even ketosis might not be enough to bring down the glucose levels far enough. This seems like a strong idea to consider.

          1. Dear J,
            I feel lucky that you entered this subject with a full energy.
            I have to expand my theory in my previous message.(My future strategy)
            I have made connections between 2 articles.
            1-Ketogenic diet:Brain will use ketones while on glucose deprivation.
            2-Oral gliflozins:Canagliflozin,dapagliflozin etc,A pre-medication for iv phlorizin.
            (May be it will reduce the dosage and time for iv phlorizin treatment.For total phlorinization.)
            They give oral dapagliflozin for 3 weeks to mice and than they give iv.After minutes there is no glucose inside the tumor.Not like in the phlorizin patent.(12-24 hours iv phlorizin treatment.)
            3-Fasting for 1 day from night to night.It is essential also in phlorizin patent.

            When she was taking IPT,mothers blood glucose down to 30,we afraid too much,Real side effects occured.
            In phlorizin patent,they dont talk about blood glucose levels.They only say there is no hypogylcemia occurs.
            I really wonder the counts after phlorinization.
            Kind Regards
            Ergin

    1. Hi Ergin,

      Surprisingly, on a strict keto diet, my blood glucose levels mainly stayed up, and I have no idea why. Even in a fasted state where I’d go to the hospital early, for some complication, and wouldn’t eat for 17-18 hours, with my last meal being a high-fat (mostly oil) smoothie, my blood glucose rarely dropped below 4.5, and most of these tests were done at the hospital with a bloodwork panel, so you can trust they’re pretty accurate.

      I did have a couple days where it was 3.2, 3.3, 3.5, etc. But those were outliers. I really don’t know why my BG level rarely dropped.

  7. very nice article Daniel and awesome discussion from all friends here , I’m still following 🙂

    I wonder if the combination of Sal + 3-BP + DCA + metformin + chemo will have any effect on highly glycolytic cancer cells ?

    its my next protocol so I just feel that I still miss a glycolysis inhibitor here

    having a weak spot in our protocol is something we should avoid

    Phlorizin is the best option , if not , then maybe dapagliflozin , or 2DG

    i should focus on this spot more than ever , this article did come in time 🙂

  8. Dear Daniel,
    Sometimes ago you told me to remember you the HSP and correlation between SGLT.
    I have found an article,it is not about cancer.
    But it makes me to thing why after hyperthermia,a sudden recovery occures.In this article the cause is SGLT1.
    If i true understand.And my thoughts are still dont change about phlorizin.
    ”Taken together, the present results show that HS(Heat stress,43 degrees for 3 hours) elevates SGLT1 activity mediated via the TGF-beta1 signaling pathway and that the increase in glucose uptake is necessary to repair plasma membrane injury.”
    http://europepmc.org/abstract/med/15577265
    Kind Regards
    Ergin

    1. Great finding Ergin! I like it a lot as it shows the connection between important mechanisms in cancer cells! The conclusion stays indeed about Phlorizin but it also indicates that for those who do not have access to Phlorizin IV but are being treated with local hyperthermia, the drugs discussed in the post above can also help to make hyperthermia more effective.

    1. Dear Helga,
      Also metfomin and sglt inhibitors can cause this.
      We need regular blood counts to prevent lactic acidosis.But please dont forget the side effects of chemo.
      And what we are dealing with.(cancer)
      Ketogenic diet is not also too innocent as you know.
      By the way,Are you still on citric acid?

      Cheers
      Ergin

      1. Dear Ergin,

        Yes, I am still on CA. I feel it is still helping me. Recently I struggle more with my lung’s mucus. I take Wobenzym also plus beta-glucan and vitamin C (it seems to help with my lung problems), propolis, sage leaves, Budwig, lansoprazole.

        How is your mom doing and how will you implement the phlorizin therapy?

        Best wishes,
        Helga

    2. Hi Helga, indeed very good point. Both phenformin and metformin are known for their capability to induce lactic acidosis. It makes sense and I would expect this to happen when using any mito inhibitors including e.g. Doxycicline.
      This makes sense to me because once mito is inhibited, cancer cells (and even normal cells) will need to upregulate glycolisis in order to compensate for the loss of energy that otherwise was produced by mito. Most cancers, but not all (e.g. those that can use acetate), are very depended on mito function since besides energy (ATP) it produces various other building blocks required for the cell division.
      Regardless, of the details since we do not know which cancer is more dependede on mito and which more on glycolisis, for each person, we must assume that both are very important and we need to address both with out treatment strategy. That is how I think.

      However, what I realize when I was reading your valuable point is that:
      1. because mito inhibitors lower the mito function, they incarease glyco – this means cancer cells will be more sensitive to proton pump inhibitors strategy http://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/ That means Metformin should be a good addition to this strategy
      2. lactic acidosis will help the chemos that are of acidic type and will not help the chemos that are of alkaline type. So we need to keep this in mind when combining Metformin with chemo, which is typical for many cancer patients

      Thanks a lot for your very good point!

      1. Hi Daniel,

        Thanks a lot. Maybe it should be a general guideline when treating cancer: one substance should be always used to prevent glycolysis (by blocking lactate, LDH, etc) and another one should be used to block the mitochondria to prevent it from producing energy. Everything else, i.e. every other cancer fighting strategy/molecule should be used on top of these two.

        best,
        Helga

  9. D, I know this might be a sensitive subject for you, though would you like to talk about the 3-BP user Peter from Australia?

    When I saw on the psi site that they made mention of his passing I was put out. There was no context to their comment. The
    implication that one would logically draw from the statement was that 3-BP had not worked for him. In fact, Peter appears to have
    very successfully coped for a number of years with metastatic illness.

    1. Dear J, thsi is indeed a sensitive subject since Peter http://petertrayhurn.blogspot.nl/ was my friend. He was such a fighter. I never saw someone more driven then him. Hi spent his last 7 years fighting cancer, mostly in Germany … may his soul rest in peace …

      Regarding Peter’s treatments, he did tried a lot of treatments. But it was too much for him. He had to be the patient and he had to be his own doctors thinking about the treatment strategies. And he had to travel from clinic to clinic across Germany and drive even when he would just be out of the hospital just a few days after surgery. Again, I never saw that strength in someone else.
      He was the master of immuno-, viro- therapies and of TACE. He has so many TACE, more than 40. That worked to stop cancer in one place but then it would come in another place …
      Some people would have been cured just with may be 10% of the treatments he used … other never … it seems there are things in this life that are beyond our control and understanding.
      Yes, as I know he also tried 3BP but just a few times in 2015 I think. But he did not continue and he only used the one from the German pharmacy that I never believed in as it was a solution ready prepared aimed to stay 1 year on the shelf. And we know the stability of 3BP is extremely low in solution at room temperature. So to me, that was nothing actually.

      During the past year, he focused on other treatments. All these treatments he used helped him to go many years further with stage IV colorectal cancer. To me, given all the treatments he did, how much we fight and the years that he survived with his difficult cancer, makes him a hero that should never be forgotten.

      If you ask me what could have been done better in terms of the treatments Pete used, I think the answer is addressing the metabolic aspect of cancer.

      That is the story as I know it J.

      Regarding 3BP some scientists think the effectiveness could depend on the blood type.

      Kind regards,
      Daniel

      1. D, yes I read in Peter’s blog that he was using 3-BP, though as you said that treatment stopped in 2015.

        I was sad to read Peter’s blog only after his passing. He was such a guiding spirit for everyone coping with cancer. I wished I had had the opportunity to suggest to him that he try minicells, X-Ray PDT, mitochondrial transfer, positive surface charge nanoparticles …. There are so many amazing cancer treatments in the preclinical or early clinical research stage. We both know that effective treatments ARE already out there, while it might take 20 or more years for them to be finally approved and widely used. I am sure that Peter would have been the type of person who could find a path to these treatments and then all the others who also were in need could also benefit.

        It also occurred to me while reading his blog that he was like a biker who was climbing a great mountain. He almost reached the top! Perhaps if the wind were more at his back or the grade were a little less steep he would have made it to the top and then he could have coasted down the mountain. From his example, I think we might reach a point with cancer therapy where people can make it to the top of the mountain and then down again.

        1. D, this is very exciting news!
          Blood group related to 3-BP response? ABO, HLA?
          Having such an easy biomarker of response could be extremely important.

          Do you have any other information about this?

  10. Hi Daniel,
    I would like to say I admire you for writing so many interesting things on this page. I don’t know how you found the time to write so many things. I couldn’t read all this evening and some things are also hard to understand for me because they are so specific to medicine field which I am not familiar with. I am sure the oncologists couldn’t possibly know so many new things because they don’t have the time to read. From what I could understand Metformin is useful also for ovarian cancer? At the pharmacy they did not want to give it to me without prescription.
    Kind regards,
    Anca

    1. Thanks a lot Anca! From your previous comment, I understand your mom is not well after this new round of chemo. I am very sorry to hear that. We can try to speak on the phone sometimes these days, probably when I am in Romania. Your family doctors should be able to give you that prescription if you explain why. I knew in Romania they are more flexible.

      Kind regards,
      Daniel

      1. Hi Daniel,
        Thank you, I will speak to you when you have the time. When are you in Romania? My mom just took 3 days of antibiotics for her boil and has so much pain in the stomach she can not handle it. She wants to interrupt taking the antibiotics after 3 days, but there is the risk of septicemia. She also had fever this evening so there infection in the body. I told her she should take the antibiotics at least five days from the seven days prescribed. She says she rather dies from septicemia than having so much pain in the stomach. What do you think, is it ok to interrupt the antibiotics after 3 days and take propolis tincture wich is a natural antibiotic?
        Kind regards, Anca

        1. Dear Anca,

          why do you think your mom would die from septicemia if she stopped the antibiotic treatment, did the doctor say so? There are a lot of natural antibiotics. Also, how about citric acid solution, maybe neutralized with sodium bicarbonate? Aloe vera, Boswellia, garlic. She could also try to take probiotics or probiotic yogurt for her stomach, as well as her immune system. Do you have Lapacho tea, cat’s claw capsules, rosemary, sage? Chamomile tea? And propolis tincture is a very good treatment, too, unless the alcohol in it bothers her skin.

          My Best,
          Helga

    2. Dear Anca,
      I’m not even a girl let alone a nice one like you 🙂
      My point to saying that is that i got metformin with the same ease someone would go buy bread with. And it’s the same country, likely the same farmacy chain.
      Persistence! Ingenuity, ambition! – Should you still have problems like that, let me know i’ll have the meds sent to you in a blink of an eye for your dear mother.
      I too have a mother suffering if you read around, and i would hate to have someone tell me i can’t do something because of system limits.
      Best Wishes,
      Alex

  11. Hi J,

    I had a long train ride today without internet and this page was open in my browser. Also the article Ergin referenced https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897486/ about “Synergistic Anti-Cancer Effect of Phenformin and Oxamate”. Very interesting combination. I finally understood why the combo needed, as phenformin and ‘biguanines’ generate lactic acid and oxamate will prevent that. Interesting that phenformin was in some cancer cultures a million times more effective than metformin! Possibly because phenformin is more soluble in lipids. I wonder how to get enough oxamate at a reasonable price? It looks like you’d need about 30 grams a day, based on the mouse treatments.

    As for depleting the cells of sugar: this is why exercise has anti-cancer effect, too. High-performing muscle cells compete for the resources (sugar) with cancer cells, no? I wonder if there are some other sugar-like molecules that can trick the cancer cells into gobbling them up mistaking them for fuel whereas they are not digested/utilized by the cancer cells, so they starve to death. I am sure Daniel wrote about anything available already.

    Best,
    Helga

  12. Taking this train of though further, this is what I found: “Treating diabetic patients, A. Braunstein observed in 1921 that in those who developed cancer, glucose secretion in the urine disappeared. One year later, R. Bierich described the remarkable accumulation of lactate in the micromilieu of tumor tissues and demonstrated lactate to be essential for invasion of melanoma cells into the surrounding tissue. One year after that Warburg began his experiments that eventually ended for him with a Nobel Prize.” http://drsircus.com/cancer/sugar-cancer-growth-research/

    Does anyone know if lactate is toxic or is it lactic acid? Or are they just indicators of cancer(ous processes)?

      1. Hi Alex, thanks for responding and your kind words! It shouldn’t be too difficult to find out.

        Actually, lactate dehydrogenase being overactive in cancers, lactate should be food/fuel for those.

        cheers,
        Helga

          1. Dear Alex,

            I have a gyn’s appointment for early June. My gp doesn’t think I have lung cancer so her sent me only to an X-ray, which I haven’t done yet. Also, you said X-ray didn’t show any tumor for your mom (how is she, by the way?). I did find some statistics that lung cancer shows with X-ray in 75% of the cases. I also read that a CT costs 2-3k US$ so maybe they want to save the costs on me. What kind of blood test would show cancer in general? What would you do if you were me? Thanks for your concern.

            Best wishes,
            Helga

            1. Dear Helga,
              As always thank you for your kind words.
              I’m certain you have a warm heart and a beautiful mind. They are so evident here.
              As for your mom possibly suffering from cancer. Let’s not be negativist. Let us allow for doubt, and place the worse possibility away from us while we search for concrete answers.
              My mother was feeling very weak as well in the past, detox was a life saver! Detox changed her life in the past, for the best. Nutrition is a major issue. We eat a lot but do not get enough of what we need.
              As for tests, rather than treating something that i may or may not have, i would like to first know what i am dealing with for certain. This would make it better in terms of knowing that it’s not cancer or confirming it.
              Know thy enemy.
              Obviously a confirmation and details of it would make it worse emotionally. I know.
              To be honest i can’t give advice, i can only express the fact that it may be best to know what is going on with a little more certainty. I say may because it’s something you on your own would have to balance pro/cons.
              Indeed the xray did not show any evident sign of a tumor, the doctors did not know what they were seeing or in this case not seeing, hence they asked for a MRI, eventually they got it and that’s when the problem became visible as if in the light of day.
              The cost in italy and romania in our personal experience was around 200 Euro-Dollars$
              With the way i think and feel, the cost is nothing compared to knowing exactly what is going on.
              For me knowing that is more important than the money. Indeed money can be an issue as i and others know.
              This again revolves around money, the best i hear is CTC (Circulating Tumor Cells) test, this should determine what cancer you have and how bad it is. – this is information that may not be correct – and i hear it costs around 800 euro in tukey, around 500 in US-Germany
              The way i hear about this test, it can determine if you have cancer even as early warning, so there may be some accuracy to it.
              To me in my mind the cost justifies the accurate and certain information for 200-800 $, more than that is indeed absurd depending on your income.
              To be optimistic, some problems can be caused by an infection of sorts, deficiencies… etc. So the tests can come back with negative signs, meaning you would be clear of any cancer.
              Once you would find out there’s nothing really life threatening i think you would then take on this information and go about enhancing good health with nutrition based strategies, this to me sounds like a good plan.
              Should the cancer be confirmed however, you would at least know who you are facing with more precision and where it is exactly situated.
              Obviously the decisions are always yours to make.

              My best wishes to you,
              Alex

              1. Dear Alex,

                Thanks for your kind and very thoughtful answer. You are absolutely right, I should push for some more accurate test. It may be small-mindedness from the doctor or my (or his) lack of conviction or indeed my fear of finding out. I have been reading about the T4 depletion strategy and something clicked in my mind: I have quite low blood pressure (111/76) and quite high pulse (80). I still may have a thyroid problem! I got it originally from a viral infection and it is still in me, I am sure. I still have a nodule in my thyroid. Didn’t people say here that low blood pressure is one of the signs that the thyroid works improperly? I can’t quite remember what exactly was being said.

                Also, it got me thinking, if T4 depletion is a strategy, then T4 is a cancer-promoting hormone? The thyroid dysfunction may also explain my extreme tendency to sweating. No doctor ever found out what is the cause (nor were they interested).

                My mom also seems to have lots of thyroid symptoms: always hungry and a tendency to bitching, whereas she was a very good-natured person in her younger years. She is very quick to judge people now and to snap. After eating something she always feels very weak and dizzy. She eats very bad (honey, butter and bread for breakfast!) but even when I made her eat more healthy, she still gets the symptoms. The only thing that seemed to help a little was a fenugreek-ginger-citric acid cocktail I made for her. I read that fenugreek has a lot of health benefits, e.g. slows down the absorption of sugar from the stomach. This is why it is used as an anti-cancer plant/spice.

                I found her artemisia! We went to a herbal shop and I saw Absinthe foliae (or something similar) and I asked the shopkeeper about Artemisia but she was not aware. I bought the Absinthe folia for my mom anyway and yesterday I googled it and it is exactly artemisia! Foliae just means leaves and the plant is the European version of Artemisia (A. absinthe) as I found out from our own dear Daniel’s article. It was used (or still is?) to make absinthe, the popular drink in the early 20th century.

                Thanks for your concerns again. I hope your mom’s treatment going well. Does she use the T4 depletion strategy?

                Best wishes,
                Helga

  13. Dear All,
    I didnt find time but after a little bit search i found that oral phlorizin also works on lowering blood glucose.
    I am sure our friends who likes searching will find more about it.
    Here is the patent of oral usage of phlorizin.
    https://www.google.com/patents/US6448232

    Emad found powder form here.
    https://www.badmonkeybotanicals.com/organic-apple-root-phloridzin-extract

    And you can monitor your urine glucose,ketone etc by test strips.100 tests costs nearly 10 usd.
    https://www.calvetsupply.com/fullsize/901/12

    I hope it helps .
    Kind Regards
    Ergin

  14. Ph on mice:

    To assess this hypothesis, we used an apple polyphenol, Ph, which has been shown to be an inhibitor of GLUT2 [[21], [22]], and determined that targeting GLUT2 significantly inhibited MDAMB-231 cancer cell proliferation and migration in vitro and in vivo. Inhibition of GLUT2 by Ph caused the cancer cells to undergo G0/G1 cell cycle arrest. The results showed that this inhibition the cytotoxic effects on cancer cells via GLUT2 inhibition was attenuated by pre-treatment with a dominant-negative p53 expression plasmid. Many previous reports have demonstrated that cancer cells have more stringent glucose requirements than normal cells. In this study, the protein level of the GLUT2 was increased in the Ph-treated MDA-MB-231 cells. We also demonstrated that the GLUT2 mRNA expression was increased in response to high glucose medium treatment. The results indicated that high GLUT2 protein expression is required for the uptake of the glucose that is present in the microenvironment. Ph treatment inhibited the glucose uptake process, and as a result, increased GLUT2 protein expression was required for cancer cell survival
    http://www.jfda-online.com/article/S1021-9498(17)30085-6/fulltext

      1. Thanks W for asking this question.
        We will find the answer alltogether.There is not too much data about it.It is not very clear for me which oral type is more effective and for which type of cancer.And the oral dosage for totally blocking glucose entry.
        What is clear for me is Cancer uses glucose for feeding,metastasis and the most interesting one is cancer uses SGLT for repairing itself.With a very simple medicine SGLT inhibitors, you can shut down the glucose entry before (for easilly killing) and after(for not giving energy to repair it self) treatments.Very effective before,during and after radiotherapy and hyperthermia.
        A team solved the problem in 1980’s.They have a protocol about total phlorizination .We can use their great experience,
        (They killed most tumors without chemo:)***
        If we carefully read the phlorizin patent,there is a great knowledge there.For example,the mice which has very big tumors are entering hyperglycemia(very low blood sugar) because tumor takes all glucose from blood.
        We can not talk about its efficiency about phlorizin protocol and patent,it is clear.
        But we can talk about this***.Is it a forgotten patent? or is it obstructed by some forces.

        For your kind question, we can use oral SGLT inhibitors by controlling urine with simple test strips.
        And we can see how much glucose we deplet.Normally no glucose in urine as we now.
        So we can monitor easily the absorption and the efficiency without danger.

        (All thanks goes to Daniel,it changed my ideas,my thoughts and my life)

        Kind Regards
        Ergin

  15. Not directly related (more complementary) to the topic… I looked into Stat3 inhibitors that could synergize with TKIs like erlotinib (and others, like gefitinib and crizotinib). Niclosamide was suggested by some articles, but it’s bioavailability isn’t great. I found another article about Atovaquone (an anti-malarial) that potently inhibits Stat3 and cancer stem cells. Also found one about Bedaquiline against CSC.

    Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent.
    https://www.ncbi.nlm.nih.gov/pubmed/27531676
    Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.
    https://www.ncbi.nlm.nih.gov/pubmed/27136895
    Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).
    https://www.ncbi.nlm.nih.gov/pubmed/27344270

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