Sometime ago, I promised to address this strategy, Shutting Down the Power House of Cancer, in more details (Ref.). Although I was looking forward to do this, it took some time to do this as I am working in parallel on three different directions, all connected. Those are the Blog (lately mainly communication in the background with people that need help), the Foundation (advancing both it’s major projects, one related to 2DG and the other related to pH in cancer), and starting up the Supplement Company (required to generate financial sustainability – the intention is to have the first products available sometimes in March 2020).
Today, I succeeded to find time to share some thoughts with you on strategies to fight cancer, with a specific focus on “Shutting Down the Power House of Cancer”, a metabolic approach to fight cancer. For some of the constant readers and friends on this website, some of the statements below may not be new. Yet, for the clarity and continuity of the discussion I need to make again some points. Thank you for your understanding.
Multiple Strategies to Fight Cancer, Chose One and Do It well
As we often discussed on this website, like any other problem, cancer can be viewed and addressed from various angles. In this way, looking for example through the lens of immune system, we could consider to address cancer as an immune system issue. In this case we will try to address all the mechanism that would help to enable or activate the immune system so that it can do it’s job and remove tumours. Another perspective we could consider, may be the hormonal perspective and try to fight caner by addressing relevant hormonal mechanisms. Or we could think of creating a pro-oxidant or an anti-oxidant pressure against cancer. Or we could decide to acidify cancer cells internally and suffocate them with their own “smoke” (Ref.). There are many ways we could fight cancer and these are just a few examples.
All these perspectives, or let’s call them strategies, are focused on attacking weak points of cancer. These are points, or mechanisms, on which cancer cells are heavily relying for their intensive activity. Now that we are aware of many such approaches, the major challenge is not anymore to find ways to beat cancer. Instead, it is about how to consolidate them in wise strategies, given a specific patient case, and how to apply them in order to increase the chance for their effectiveness.
Several such strategies that I intend to address in various posts to come are depicted in the figure below, indicated by the Blue-coloured hexagons. Aspects that I see them more as supportive and that would be addressed in parallel with the main strategies, are represented by Mustard-coloured hexagons. The strategies highlighted in the hexagons do not represent just one mechanism but multiple mechanisms clustered under the same umbrella. For example, “Inhibiting Cellular Building Blocks” includes anti cholesterol production too, previously discussed on this website. Mechanisms such as authophagy and angio-genesis are included in the “Deplete Nutrients” strategy. Nevertheless, with this figure, I did not intended to cover all possible strategies to fight cancer. Instead, my purpose was to create an overview of the major strategies I find relevant and I like to address in various posts to come.
The strategy we chose should be inline with the core treatment we decide to have. For example, if we go for Chemotherapy or Radiotherapy we may chose the pro-oxidant strategy as our Central strategy, and build our treatments around that, while if we go for angio-genesis inhibitor drugs, we may want to focus on the “Nutrient Depletion” strategy as top priority.
The idea is to align/integrate our core treatments (often defined by oncologists) with a Central strategy that is likely to add more value that the core treatment alone. If there is no core treatment that we are planning to use, we will chose a Central strategy and try to make that as strong as possible including repurposed drugs and supplements (oral and intravenous when possible). Therefore, I think what is essential is the fight against cancer is to be consistent, coherent and have priorities.
Integrating treatments in a coherent manner, to create cocktails, it is actually a trend in the oncology industry, also reflected by many of the recent clinical trails that now include two or more drugs. It is a trend generated by the need to improve the current treatment methods that have limited effectiveness.
Furthermore, I am constantly stressing the point about consistency, coherency, and priority because as cancer patients become more and more aware of the potential to fight cancer as a metabolic disease, there is a tendency for the patients to try inhibit all possible survival pathways at the same time. However, in reality this is difficult to achieve if not impossible because of two major reasons: first, it is likely we do not know all the surviving pathways of cancer; second, to get a fair chance for inhibition, each mechanism requires high dose of supplements/drugs, and that multiplied with the number of mechanisms to address leads too a very high number of capsules/tablets that would be impossible to take for most patients. As a result, patients trying to address all escape routes, will end up with a low dose of supplements/drugs for each target that may not hep much.
This is why, while in theory I would like to address everything at the same time, in reality it would help people to have a logical way to identify priorities as a function of the treatments given by their oncologist or a function of their choices. On this line, a better route in my view is to select one strategy that is relatively well understood scientifically, which would address a key mechanism in cancer, and address that seriously with higher doses of drugs and supplements. If there is space for more drugs and supplements, and the patient can take more tablets, we can include other strategies that work well together with our selected and Central strategy, as I will discuss below.
Shutting Down the Power House of Cancer as a Central Strategy
One (metabolic) strategy that could be chosen as the high-priority strategy is to “Shut Down the Energy Engines” responsible for the energy production in cancer cells. In this case we just need to focus on “shutting down” the energy factories of the cell. Fortunately, this is not very complex as there are only two energy factories inside the cells:
- respiration via mithocondria
- fermentation in the cytosol
Once I would chose this strategy and mechanisms as a priority I prefer to address this strategy intensively, and place the inhibition of fatty acids, glutamine and glucose on a lower priority level. This is because, glucose, glutamine and fatty acids require functional engines (respiration and fermentation) in order to be converted in energy (ATP). So, for example if we shut down the respiration (the engine), there is no way glutamine (the fuel) will be converted in to energy.
(I should note here, that when we speak about “inhibition” or “shutting down” that will not happen literary, instead in general the activity of the specific target will be reduced only, but to a level that seriously affects cancer and not normal cells)
Indeed, various studies have demonstrated that concomitant inhibition of fermentation and respiration is lethal to most cancer types but not to normal cells. Here are just a few examples of those studies:
- Fermentation inhibitor Gossypol + Respiration inhibitor Phenformin: ALDH inhibition using gossypol, combined with mitochondrial complex I inhibition using phenformin, resulted in up to 80% depletion of ATP production in cancer cells, accompanied by significant growth regression of NSCLC tumors in the animal xenograft model, while normal cells do not have a loss of ATP production (Ref.)
- Fermentation inhibitor + Respiration inhibitor Metformin: Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells (Ref)
- Fermentation inhibitor Diclofenac or Diflunisal + Respiration inhibitor Metformin: Combined Metabolic Targeting With Metformin and the NSAIDs Diflunisal and Diclofenac Induces Apoptosis in Acute Myeloid Leukemia Cells (Ref.)
- Fermentation inhibitor Diclofenac + Respiration inhibitor Metformin: Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma (Ref.)
- Fermentation inhibitor Oxamate+ Respiration inhibitor Phenformin: Synergistic Anti-Cancer Effect of Phenformin and Oxamate (Ref.)
- Fermentation inhibitor Syrosingopine + Respiration inhibitor Metformin: Syrosingopine sensitizes cancer cells to killing by metformin (Ref.)
- Fermentation inhibitor 2-Deoxyglucose + Respiration inhibitor Metformin: Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism (Ref.)
- Fermentation inhibitor 2-Deoxyglucose + Respiration inhibitor Metformin: Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. (Ref.)
- Fermentation inhibitor Vitamin C + Respiration inhibitor Doxycycline: Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs) (Ref.)
- Fermentation inhibitor Vitamin C + Respiration inhibitor Doxycycline and Azithromycin: Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs) (Ref.)
- Fermentation inhibitor Vitamin C + Respiration inhibitor Berberine: Dodecyl-TPP Targets Mitochondria and Potently Eradicates Cancer Stem Cells (CSCs): Synergy With FDA-Approved Drugs and Natural Compounds (Vitamin C and Berberine) (Ref.)
Therefore, combining inhibitors of fermentation and of respiration is one of the very relevant strategies to fight cancer. An actionable plan along this strategy can be put in place relatively fast given that we (contributors to this website and myself) already collected long lists of accessible fermentation inhibitors and respiration inhibitors shared on this website at the following links:
In order to try addressing each of these two mechanisms effectively, I would consider addressing them with at least 2 or 3 inhibitors each, at the same time, using a dose that we expect it may be effective in reaching the goal. In my view, looking at drugs and supplements that can be take orally, we do have more effective tools to inhibit respiration compared to fermentation. This is why, I would use two/three respiration inhibitors and a larger number of fermentation inhibitors (including glucose transporter inhibitors). Below is a picture showing a basic strategy to shut down the energy engines.
Note on the figure above:
- For each drug or supplement, only the major targets relevant to this strategy are mentioned (otherwise most of the drugs and supplements have multiple targets, e.g. Metformin also affects fermentation, Canagliflozin also affects mitochondria)
- Blue-coloured hexagons represent repurposed drugs while Moustard-coloured hexagons represent natural extracts
Example of daily doses that I would consider on the above (oral administration):
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I would always start each drug an supplement step by step towards the target dose, and not all at once. For example I would add one new drug or supplement every two days (to identify any undesired reaction if any) and increase towards the target dose during e.g. two weeks.
As indicated in the figure below, in order to further improved the above strategy, I would also consider the addition of intravenous administration of:
In case this strategy is combined with chemotherapy, I would stop all fermentation inhibitors 3 days before chemo (including Metformin/Berberine as it also affects fermentation but not Doxycicline or Atorvaquone), and restart them in the day of chemo, starting with Metformin during the chemo day, and the others building them back up step by step. The first to restart are re-purposed drugs, and about 3 days after the plant extracts such as Quercetin and EGCG. Omega 3, I would keep it ON continuously.
In case this strategy is combined with radio-therapy, I would stop all plant extracts 3 days before radio and restart them about 3 days after. All the others, including Omega 3, and specifically respiration inhibitors, I would keep ON.
Note that the combination of Meformin and Syrosingopine has been explored intensively during the past months as some of the patients around the world are implementing this combo and some on our forum and the Inspire forum are possibly seeing positive results (Ref.).
If High Dose Vitamin C treatment is performed, I would avoid taking GLUT1 inhibitors (such as Caffeine and others) several hours prior to Vitamin C administration since GLUT1 transporters are required for the absorption of Vitamin C inside cancer cells (Ref.).
Extending “Shut Down Energy Engines” Strategy
In the Figure below, “Shut Down Energy Engines” strategy is depicted at the main strategy, and at the right side, in order of priority there are other strategies that are considered as having good potential to support our main strategy. Of-course, this picture would change if we would chose another Central strategy instead of “Shut Down Energy Engines”.
If I would look for ways to further improve the above strategy, the first strategy to consider as a good addition is the strategy to acidify the cancer cells. This strategy has been specifically discussed here.
Adding “Acidify Cancer Cell” strategy to enhance “Shut Down Energy Engines” strategy
Why I think this is a good idea? The strategy focused on “Shut Down Energy Engines” included respiration inhibitors. Inhibiting respiration effectively, redirects energy production on the fermentation path, and if that will still be active (i.e. not effectively inhibited by our supplements and drugs), cancer cells will produce large amount of protons (acidity) that need to be exported in order to avoid the cancer cell death. In other words, it is possible for cancers to use fermentation as an escape route. If this is the case, inhibiting the transporters/mechanisms used by cancer cells to push the protons outside the cell will lead to accumulation of protons (acidity) inside the cancer cell, shut down of fermentation and finally cancer cell death.
It makes also very much sense to consider “Acidify Cancer Cell” as a next strategy to add, given the large overlap of drugs and supplements required for the two strategies, i.e. for “Shut Down Energy Engines” and “Acidify Cancer Cell”. For example, Metformin, Doxycicline, Quercetin, Statins, Syrosingopine, Diclofenac are already known as cell acidifies. So it would only required at least one, possibly two other drugs to address “Acidify Cancer Cell” strategy relatively well. Those repurposed drugs are:
- Amiloride (as a Na/H exchange inhibitors) read more here on the doses (Note: when using Amiloride, blood levels of potassium have to be verified every two weeks to make sure it doesn’t go to dangerous levels)
- Acetozolamide (as a CA IX inhibitors) read more here on the doses
Other approaches that could enhance “Shut Down Energy Engines” strategy
Increasing intracellular acidity also inhibits fermentation (Ref.), inhibits β-Catenin (Ref.), inhibits mTOR (Ref.) and triggers authophagy (Ref.). However, if the strategies above are addressed well, tumours will be destroyed regardless of autophagy. Nevertheless, if one would want to also address autophagy it would make sense to consider Hydroxychloroquine at about 200mg/day (due to it’s long half life, taking it even every few days make do it’s job). Normally, Hydroxychloroquine has serious challenges in reaching the tumor location due to the typically acidity around the tumors combined with it’s weak-base profile – acidity around the tumor will protonate Hydroxychloroquine. However, when combining Hydroxychloroquine with the strategies above protonation may not be the challenge anymore, since the fermentation is reduced or protons accumulated inside the cancer cells. Note that in my view, Hydroxychloroquine is part of the Nutrient Depletion strategy.
Going further on extending “Shut Down Energy Engines” strategy, we could also consider adding at least part of the “Cellular Building Blocks inhibition” with a specific focus on addressing Cholesterol production. This also makes sense to consider in extension of “Shut Down Energy Engines” strategy since again, there is a good amount of overlap of the supplements and drugs used for the two strategies, i.e. “Shut Down Energy Engines” and “Cellular Building Blocks inhibition”. More specifically, Cholesterol production inhibition also includes Satins, Metformin, Doxycicline, Omega 3, Berberine as discussed here (Ref.). To further complete this strategy, I would consider adding HCA and Dipyridamole. Dypiridamole and HCA daily doses are discussed here (Ref.).
In summary, an extension the “Shut Down Energy Engines” strategy, would contain
- at least on of the proton pump inhibitors Amiloride or Acetozolamide, preferably both
- the authophagy inhibitor Hydroxychloroquine
- HCA and if possible Dypiridamole
Finally, regardless of the treatment strategy, in parallel to the central strategy, I would always consider using drugs and supplements to
- address parasites and inhibit fast cell division, such as Mebendazole
- reduce inflammation and inhibit metastasis such as Curcumin, baby Aspirin and Olive Leaf Extract
- support vital organs and immune system such as Vitamin D, Milk Thistle and Astragalus
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