Modulating the Yin and Yang Energy of Cells to Fight Cancer: Pro-Oxidant Strategy

First, An Update

Dear Friends,

Coronavirus took a lot of our attention lately (Ref.1, Ref.2), and probably we will address it more in the future as it is important for all of us to be aware of ways to address it if needed. I think we do have a good idea now on how to respond to it, and as we’ve seen most of the drugs and supplements relevant for the fight against Coronavirus are also those relevant against cancer, many of which we have discussed for years on this website.

I know it is so difficult for the cancer patients during these times, as it is more challenging to have the required medical attention and more difficult to obtain the required drugs.  If there is anything positive in all this mess that Coronavirus created around the world taking the life of so many people and reducing our access to medical care, is that as we move forward the awareness and openness of the society towards accepting and implementing fast repurposed drugs is much higher now.

It is now becoming clear for all why we, the oncology patients and care-givers and all the innovative scientists and medical doctors, have investigated and promoted so much the use of re-purposed drugs in oncology. They see how repurposed drugs such as Hydroxychloroquine can save life of Coronavirus patients, as we knew the same drug (and other re-purposed drugs) could save life of cancer patients. So let’s hope that this mess created by the Coronavirus will finally lead to a better world for the cancer patients.

With this post, I would like to share with you a view on  how to modulate the intra-cellular level of Anti-Oxidants and Pro-oxidants as a strategy to fight cancer. I will discuss re-purposed drugs, supplements, chemo- and radio-therapy.  As a result, the focus of this post is on increasing pro-oxidant level in cancer cells to fight cancer.

Before going to the main subject of this post, I would also like to take the chance to update you on what I was (and I am) working on during the past months and the related results.

In order to be able to move things forward I had to temporarily slow down in writing posts on this website. While I wish I could write more, and I have a lot to say, there are only 24 hours/day and nearly every day, about 17 of those I allocate to moving forward the Blog, the Foundation and the Food Supplement Company. I am glad to say that on all lines there is very nice progress:

  • The Blog: next to all the daily communication mostly on the e-mail with people fighting cancer, since recently we have a new section to this website entitled “View in Oncology“. This is a section dedicated to scientists and clinicians, who have to share with the World unique views that add important value to our goal: to improve and extend life of cancer patients. During the past months, we already had two authors published in this section, and there will be more to come soon from valuable experts in the field. .
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  • The Foundation: there are two major projects running in the non-profit organisation MCS Foundation For Life: one project is on proton pump inhibitors as a way to fight cancer and another on glycolisis inhibitors to fight cancer. I will detail them as soon as I find the time at www.mcsfoundationforlife.com. I am glad to say that along these projects we recently succeed to have a new scientific paper published in collaboration with scientist, some working on this subjects for more than 30 years. Here is the paper recently published A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics. With this, for the first time, the name of the Foundation is on a scientific paper. In addition, in the project along the glycolisis inhibitor line we are now interacting with important scientists and contributors in the field of transnational medicine, representing some of the best medical schools in the world, with the goal to move metronomic 2DG to clinical trials. Moving to clinical trial takes time, specifically when there are financial limitations, but the project is moving forward and that is very important.
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  • The Supplement Company: As you know, my goal is to put in place a successful food supplement company that could offer valuable products to people. Even more important is that with such a company we can allocated a major part of the profits back to projects that can improve and extend life of cancer patients. Probably a lot of this will go in re-purposed drugs and natural extracts for oncology, that can be implemented on short term. There are so many academic discoveries that are not reaching patients just because there is no business sense behind. Imagine how beautiful would be to have a large company that gives a large part of its profits to support the translation of valuable academic discoveries to people! How great it would be when the whole registered community here and those people buying the supplements can decided where to inject those money! That is what we are going to have and I am working on intensively on the start-up (with a few other colleagues driven by the same goal) – I promise in April/May the company will be up and running. With that, we will be able to do so much more towards improving and extending life of cancer patients, and in that process we will involve the community here.
    .
    In line with the foundation, the name of the food supplement company recently established is MCS Formulas. .

This was the short update from my side. Now I’ll move to the main subject of this post:

Why and When Up-regulating Pro-Oxidant level in Cancer Cells Makes Sense

The strategy I will discuss below is part of the strategy-series that I started publishing at the end of last year, and intend to continue addressing throughout the coming year. These strategies are focused on addressing weak points of cancer cells.

As a reminder, at the end of last year, we discussed about the strategy focused on “shutting down” the two engines responsible for energy production in cancer cells: Shutting Down The Power House of Cancer. This could be one way to fight cancer with on a cocktail of drugs and supplements, as a stand alone strategy or as support for other core treatments.

Another important weak point (or bottleneck) of cancer cells is related to the balance of anti-oxidant/pro-oxidant level inside the cells, or as mentioned in the title: “the Yin and Yang energy of the cell”.

Essentially, anti-oxidants are electron givers/donors and pro-oxidants are electron receivers/takers. That is the whole difference between the two. A good balance of the givers and the takers inside cells, ensures normal survival of the cells regardless if we speak about cancer or normal cells. However, the difference between normal and cancer cells is that the population of givers and the takers is much higher in cancer cells.

The pro-oxidants, or the takers, are also called Reactive Oxygen Species, on short ROS. All living cells generate ROS while metabolizing oxygen. ROS generated during the normal life of a cell are e.g. superoxide, hydroxyl radicals, hydrogen peroxide. Therefore ROS generation is an integral part of normal cellular function, and ROS such as hydrogen peroxide (H2O2) are involved not only in immune response and oxidative stress, but also as a physiological influence of essential cellular processes (Ref.). Thus, ROS is good in normal amounts.

However, in high amounts ROS can damage and even destroy the cell. So like everything in life, too much of something is not good. When too much ROS is present in the cell, in order to protect the cell, a regulator is activated called Nrf2. This, in turn, up-regulates the anti-oxidant cell defence system that can deactivate ROS. The anti-oxidant cell defence system includes anti-oxidants such as Glutathione, Thioredoxin, Catalase and others that are listed in “Details” section at the end of this post.

Due to various reasons specific to tumors (including increased metabolic rate, tumor hypoxia, lower pH), production of ROS is elevated in malignant compared to normal cells. In order to cope with this and insure their survival, tumors upregulate levels of antioxidant enzymes and successfully counteract increased oxidative stress (Ref.), which would otherwise lead to chain reactions in lipid layers, and damage DNA repair enzymes (Ref.). Therefore, same as in normal cells anti-oxidants protect cancer cells, helping their continuity and resistance to conventional treatments.

As a side but important note, I would like to mention that some experts in integrative oncology see high intracellular ROS at the origin of cancer and not the outcome of cancer. Along that line, it is proposed that ROS is mainly generated by not properly functioning mitochondria. Going further, it has been argued that restoring the normal function of mitochondria could help turn cancer cells into normal cells. In my view, this is a relevant perspective to consider, that can take us towards another strategy to fight cancer, specifically focused on antioxidants, which I intend to address in another post.

In my view, both pushing up the anti-oxidants or pushing up the pro-oxidant level can be a way to fight cancer, as long as we do that in a consistent manner. Therefore, in another post, I will discuss why fighting cancer with anti-oxidants makes sense as well and can be a powerful approach. 

Yet, in this post, I would like to build on the fact that due to various reasons mentioned above, in tumors the level of ROS is high and that is pushed to even higher levels when patients undergo pro-oxidant treatments such as chemo- or radio-therapy. This makes ROS an important weak point of tumors, specifically when patients undergo conventional treatments.

Imagine we have a glass full of water (that are the tumors full of ROS when patients are given chemo/radio or other pro-oxidant treatments) and we only need to add an extra drop for the water to go over the brim and spill out. This is the strategy I want to address in this post and the extra drop of water will consist of supplements and re-purposed drugs that will create the extra ROS required for the tumours to hopefully die.

Indeed both therapeutic- and the side-effects of ionizing radiation during radiotherapy and of chemotherapy are mainly due to the generation of ROS, that in turn interact inside targeted cells with the cell DNA (Ref.). Hopefully, the generated ROS exceeds the anti-oxidant production capacity of cancerous tissue, leading ultimately to apoptosis or necrosis. And hopefully, because normal cells have a lower initial ROS level, they will manage to survive during the conventional treatments. Various conventional therapies such as monoclonal antibodies and TKIs also seem to have many ROS-mediated anti-cancer mechanisms of action (Ref.). Same applies to many treatments discussed on this website including Taurolidine, High Dose Vitamin CArtemisinin.

Therefore, in contrast to the whole concept of extending life and protecting cells with anti-oxidants, when fighting cancer a pro-oxidant strategy can make sense. It may support treatments such as radiotherapy and of chemotherapy, and could therefore be a great approach to increase the chance of effectiveness of anti-cancer treatment.

Nevertheless, even if the normal cells will cope much better with pro-oxidants compared to cancer cells, I do not like the idea to continuously expose the body to pro-oxidant treatments. This is why I see this strategy as a pulsed strategy to be implemented around the pro-oxidant treatments such as radiotherapy and chemotherapy sessions, or around other core treatments that are of a pro-oxidant nature (including High Dose Vitamin CArtemisinin, Taurolidine and others).

Between those sessions, focused on increasing the pro-oxidant level, we can also consider detox cycles including anti-oxidants as long as those are used several days away from chemo/radio.

Modulating the Yin and Yang Energy of Cells to Fight Cancer: The Concept

According to the above discussion, with this Pro-Oxidant strategy our goal is to increase ROS in cancer cells to a level that is not sustainable for cancer cells. Most but not all of the ROS-increasing approaches discussed below are not selective to cancer cells alone, and will induce oxidant pressure on both the normal and the cancer cells. However, since normal cells have initially a lower ROS level, they will be able to cope much better with pro-oxidants compared to cancer cells. In order to increase intracellular ROS we can act on the following lines:

  1. Reduce the intracellular antioxidants
  2. Increase intracellular ROS (reactive oxygen species)

Reducing antioxidant level can be done in the following way:

  • reduce the fuel for anti-oxidant production. There are both direct and indirect fuels
    • indirect fuels required for the anti-oxidant production (or let’s call this “the fuel of the fuel”) are e.g. Glucose, Glutamine, Methionine
    • direct fuels used to produce anti-oxidants are e.g. Cysteine, NADPH, Glutamate
  • reduce the activity of anti-oxidant production systems (such as, but not only, Thioredoxin system) and reduce anti-oxidants
  • reduce the activity of the anti-oxidant master regulator NRF2

These major targets (excluding indirect fuels) are depicted in the figure below.

The yellow highlight hexagons in the figure above will be our targets, that we want to modulate and down regulate, as a part of the pro-oxidant strategy. I will discuss latter in this post what are the drugs and supplements that can help us modulate most of these targets.

However, note that besides these major approaches to reduce anti-oxidants, it is also possible to reduce anti-oxidant action by e.g. inhibiting the action of anti-oxidants. For example, one natural extract that is on top of my preferred list, Piperlogumine (that is the major component in Long Pepper), suppresses glutathione S-transferases (GSTs) that enables the anti-oxidant action of glutathione. Glutathione S-transferases (GSTs) is one of the enzymes know for inducing drug resistance to anticancer agents (Ref.1, Ref.2, Ref.3). Piperlogumine has also been found as glutathione depletor. Acetaminophen is another glutathione depletor – it is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), which reacts with glutathione and can trigger glutathione depletion.

While the above may look a little complex, that doesn’t have to be the case. We do not have to modulate all of the above. But obviously, the more we address the higher the chance of achieving our goal is.

Increasing intracellular ROS is a more straightforward approach. As discussed above, that can be achieved directly with e.g. high dose Vitamin C treatment that can generate ROS or with chemo or radio-therapy.

Nevertheless, besides these direct and more obvious ROS generating approaches, another approach that can help generate ROS is either by increasing mitochondria activity, or by reducing mitochondria activity. This is counter intuitive and the reason both can work is the following:

  • during it’s normal function, mitochondria produces ROS (complexes I and III produce the majority of mitochondrial ROS) (Ref.). Increasing it’s function, naturally will lead to increased ROS
  • on the other hand, when mitochondria is inhibited with mitochondria inhibitors, this induces incomplete electron transfer to oxygen that can lead to the formation of additional ROS (Ref.1, Ref.2. Ref.3). However, this is not always the case as it depends on the mitochondria inhibitor type and on the respiratory-chain substrates to determine if they will increase or reduce ROS (Ref.). Therefore, in general I would not rely on mitochondria inhibitors to do the job as a part of this strategy, unless we know exactly what we are doing. Nevertheless, in combo with radiation I would specifically use them since mitochondria inhibitors such as Atorvaqone (malaria drug) can induce a rapid decrease in oxygen consumption by the tumors and as a result increase the availability of oxygen inside the tumor, restoring the ability of oxygen to act as a radiosensitizer (Ref.).

According to this, in order to increase intracellular ROS we could also focus on inhibiting fermentation with fermentation inhibitors. This is because, when there is too much ROS produced by mitochondria (due to high energy demands), malignant cells start adopting a fermentation-based (glycolytic) energy production that in turn reduces the mitochondrial function and the related ROS production. By inhibiting fermentation, malignant cells have no other option than producing energy via mitochondria, which leads to an increase in the intra-cellular level of ROS, that is our goal in the strategy discussed here.

One way for cancer cells to switch energy production from mitochondria to fermentation, is by activating an enzyme called pyruvate dehydrogenase kinase (PDK). Indeed, it has been shown that inhibition of PDK enzyme induces cell death through increased mitochondria activity and subsequent ROS production (Ref.). This can be achieved with an existing drug, available and cheap, called DCA (Ref.). Furthermore, it has been shown that re-activating mitochondria with DCA while interfering with mitochondrial complexes I, with the help of Metformin, can further enhance ROS production (Ref.), that is inline with our discussion above.

Therefore, reducing the anti-oxidant level in cells increases the chance of pro-oxidant treatments (ROS inducing treatments) effectiveness. By doing this we are actually addressing one of the major drug resistance mechanism of tumours, that is related to the capability of tumors to increase anti-oxidants as soon as pro-oxidant treatments attack them. This is the reason why oncologist recommend patients not to use anti-oxidants while on chemo or radio-therapy. Indeed, this is not a theory only: I’ve seen on CT scan how, when antioxidants are given intravenously a few days after pro-oxidant treatments, they rescue the tumors and they continue to be active, while the tumors  treated with pro-oxidant treatment alone did not progressed. Even if the chemo is out of blood, or radiation has been done some days ago, their pro-oxidant effect is still doing the job days after their application. So I would always stay away from anti-oxidants some days after chemo/radio.

In my view, the anti-oxidants that should be avoided during chemo/radio and only give a week away from chemo or latter, are Glutathione intravenous or oral, Alpha Lipoic Acid intravenous or oral, NAC, Vitamin E, SOD. This dose not apply to most of the plant extracts, that have limited anti-oxidant potential in humans at the tumor level, and actually many of them have a pro-oxidant action in cancer (Ref.) next to many other beneficial effects.

As it will also become evident in the discussion below, plant extracts such as Curcumin, Quercetin, EGCG, Piperlogumine, etc. can inhibit the production of anti-oxidant enzymes inside cancer cells. This makes them effectively act as pro-oxidants even if the are often refereed to as antioxidants. In addition to this, it has been shown that plant food constituents such as polyphenols can act as pro-oxidants in the following conditions:

  • at high dose
  • inside cells that contain high amounts of e.g. Iron or Copper ions (which is the case of cancer cells)
  • in cells that have high level of pH (which again is the case of intracellular space in cancer cells) 

For more discussion on the above please see the following reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952083/

This is the reason why, as I will further discuss latter in this post, I see “anti-oxidants” split into two major categories:

  • strong-anti-oxidants (to be avoided in the strategy discussed in this post and in general should not be combined with chemo/radio)
  • anti-oxidants known to have pro-oxidant effects – this is the category including plant extracts like Curcumin, Quercetin etc. and in my view they can be combined with chemo/radio but I would use them some days away from chemo/radio.

Indeed, Curcumin intravenous is often used at cancer clinics around the world and with good results in combo with Chemo- and Radio-therapy. Nevertheless, I would always start to use them some days latter (e.g. 3 days) and not immediately with or after Chemo- and Radio-therapy.

Coming back to anti-oxidant inhibitors, indeed, various studies have demonstrated that concomitant inhibition of anti-oxidant inhibitors (such as Sulfasalazin, Auranofin, etc.) next to pro-oxidant treatments is lethal to most cancer types but not to normal cells. Here are some examples of those studies:

There are thousand of papers, and therefore large amount of scientific literature, supporting the fact that inhibition of anti-oxidants can increase the effectiveness of pro-oxidant treatments including alternative and conventional treatments, in all cancer types.

Modulating the Yin and Yang Energy of Cells to Fight Cancer: The Tools

Now that it is clear the anti-oxidant depletion can support the effectiveness of pro-oxidant therapies, the question would be what are the targets that can help us inhibit the anti-oxidants and what are the pro-oxidant treatment that we can have in mind to use as core treatments, or in general as a component of this strategy. Bellow, I will address the major targets and the drugs and supplements that can modulate those in a structured manner, but without explaining each target since otherwise this post would become extremely long:

Reducing antioxidant level can be done with the following drugs and supplements:

    • reduce the direct fuel for anti-oxidant production:
        • Drugs and supplements reducing Cysteine: Sulfasalazine (x(c) (-) inhibitor) (Ref.) Sorafenib & Erastin (x(c) (-) inhibitors) (Ref.)
        • Drugs and supplements reducing NADPH: DHEA (PPP inhibitor) (Ref.), Polydatin (PPP inhibitor) (Ref.), EGCG (PPP inhibitor) (Ref.), Rosmarinic acid (PPP inhibitor) (Ref.)
        • Drugs and supplements reducing Glutamate: BPTES (as GLS inhibitor) (Ref.)
    • reduce the activity of anti-oxidant production systems and reduce anti-oxidants
        • Drugs and supplements reducing Thioredoxin: Auranofin (TrxR inhibitor) (Ref.), Curcumin (TrxR inhibitor) (Ref.), EGCG (TrxR inhibitor) (Ref.), Quercetin (TrxR inhibitor) (Ref.)
        • Drugs and supplements reducing Glutathione: Tiopronin (inhibition of glutathione peroxidase (GPx))(Ref.), Methylglyoxal (inhibition of glutathione peroxidase (GPx))(Ref.), BSO (glutamate cysteine ligase inhibitor)(Ref.), Piperlogumine (glutathione transferase inhibitor) (Ref.), Paracetamol/Acetaminophen (glutathione depletion) (Ref.), Statins (inhibition of glutathione peroxidase (GPx))(Ref.), Ethacrynic acid (glutathione transferase inhibitor) (Ref.), Pyruvinium pamoate (inhibits glutathione supply from stromal cells) (Ref.), DHA from Omega 3 oil (intracellular GSH depletion) (Ref.), Fenbendazole (glutathione depletion) (Ref.)
        • Drugs and supplements reducing SOD: Tetrathiomolybdate (reduces SOD) (Ref.), Disulfiram (reduces SOD) (Ref.), Salinomycin (reduces SOD) (Ref.)
        • Drugs and supplements reducing Catalase: EGCG (Ref.1, Ref.2), Myricetin (Ref.)
        • Drugs and supplements reducing Peroxiredoxins: effective and available inhibitors to be found
    • reduce the activity of the anti-oxidant master regulator NRF2
        • Reducing NRF2: Disulfiram (reduces NRF2) (Ref.), Retinoic acid (reduces NRF2) (Ref.), Isoniazid (reduces NRF2) (Ref.), Valproic Acid (reduces NRF2) (Ref.), Metformin (reduces NRF2) (Ref.)

Other ways to reduce the fuel for anti-oxidant production is by reducing the indirect fuel or “the fuel of the fuel”. This can be addressed in the following way:

        • Reducing Glucose: diet (reduce sugar, carbohydrates), 2DG, 3BP, Canagliflozin, Phlorezin, Ritonavir
        • Reducing Glutamine: diet (reduce red meat), Phenyl Butyrate
        • Reducing Methionine: diet (reduce eggs, meat, and fish, sesame seeds)

Increasing intracellular ROS can be achieved with some of the following

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Modulating the Yin and Yang Energy of Cells to Fight Cancer: The Application

With the above list I did not tried to be complete but highlight some of the most relevant targets and available tools to modulate them. As we can see from the above, there are many drugs and supplements that have the capability to support chemotherapy and radiotherapy, or that can be used alone to build a strong treatment cocktail. The figure below shows an example of how I would consolidate some of them together.

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)
  • 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.

The figure above shows a cluster of drugs and supplements that I selected as priority. However, this doesn’t mean that all should be used. Even if only one of the above drugs is used to support chemo or radiotherapy, it should still be helpful. Of course, preferably all should be used if that is possible. On the right side of the figure I also highlighted “other options” for the selected drugs/supplements, that could represent alternatives for Sulfasalazine, Auranofin, Canagliflozin, Retinoic Acid, Piperlogumin, Polydatin.

Notes:

  • sulfasalazine treatment may induce brain edema in brain cancer patients (Ref.) so it would be best to avoid it in this case
  • I would avoid using DHEA when the patients deal with a hormonal cancer, and clearly not use it in prostate cancer

Note that in my experience, using high levels of DHEA alone to address the anti-oxidant production is not effective enough. This is evidenced by functional adrenocortical tumors that produce very high levels of DHEA in patients, while these tumors are very aggressive and resistant to chemo. This non-effectiveness of DHEA alone may be explained by two facts: either DHEA is converted very fast in hormones (this is an argument often used in the literature), or tumours find other ways  to generate NADPH (that is inhibited by DHEA when inhibiting PPP pathway). Indeed, I think the challenge is the latter, since PPP is responsible for generation of about 20% of NADPH. Most of NADPH is generated via other pathways such as 10-formyl-THF. Nevertheless, addressing anti-oxidant production with DHEA next to all the other drugs and supplements listed above will certainly increase the chance of achieving our goal.

Of the above drugs, in my view, Auranofin, Sulfasalazin and Retinoic Acid stand out in their capability to inhibit the anti-oxidant production, and these would be the first I would consider to use to support chemo or radio. If not available, there are many still relevant options listed above. Disulfiram is also one drug that stands out in the fight against cancer. However, the challenge related to this is the fact that once the patient is taking it, no alcohol can be used anymore – in some cases this may represent a challenge since some intravenous drugs that the patient may need could contain ethanol.

In order to apply the above strategy I would first consider what is my core/central treatment. If chemo or radio is the core treatment, I would apply this strategy in the following way, as an example:

  • the drugs use to reduce anti-oxidants: I would start a few days before chemo/radio (e.g. 2-3 days) until several days after chemo/radio (e.g. 5-7 days); a few of them can be continued for longer time, but too many at the same time for too long time may be too heavy for the body.
  • the food supplements (such as Curcumin, EGCG, Quercetin, Piperlogumine, and others mentioned above) can be applied continuously, with a short brake starting a few days before chemo/radio (2-3 days) and until a few days after (2-3 days). While we expect that the supplements above will add value to this strategy (and I would feel safe even maintaining them) given their potential for pro-oxidant action, I may stop them just to be 100% we do not interfere with chemo/radio.
  • in between chemo/radio sessions I would use High dose Vitamin C and Artesunate, all intravenous, if available. Curcumin and Quercetin intravenous would also fit here as well as Ozone therapy, Salinomyin, DCA and other ROS generating treatments. 
  • during all the time without pause I would take silver nano-particles and Omega 3. Artemisia Annua tea or capsules and Artemisinin capsules could also be used during this time, according to the procedure discussed here.
  • no strong anti-oxidants should be used a few days before and about 7 days after chemo/radio. By strong antioxidants,  understand N-acetylcysteine (NAC), Glutathione, Alpha Lipoic Acid, Vitamin E.

Note: a few lines above have been changed compared to the version initially published to accommodate some discussions regarding the safety of using supplements such as Curcumin, EGCG, Quercetin, Piperlogumine during the chemo day.

So essentially, for food supplements I would apply the following rule:

  • strong anti-oxidants like NAC, ALA, etc. should not be taken 6-7 days before and after chemo;
  • anti-oxidants known to have pro-oxidant effects (like Quercetin, Curcumin, etc.) should not be taken 2-3 days before and after chemo
  • pro-oxidants or others widely known to bring good benefit to radio/chemo can be continued during chemo/radio. Examples are: Omega 3, Aremisia Annua, Silver Solution.

Therefore, the anti-oxidant reduction strategy (and more specifically the re-purposed drugs in this strategy) is applied in pulses around chemo. The supplements and the additional intravenous treatments are added to support this strategy and can be used in a more continuous manner.

If chemo is taken in a more continuous way and not pulsed (such as it is the case for oral chemo drugs), for the food supplements I would apply the following approach:

  • strong anti-oxidants like NAC, ALA, etc. should just be avoided;
  • anti-oxidants known to have pro-oxidant effects (like Quercetin, Curcumin, etc.) will be used in cycles such as 2 weeks ON and 2 weeks OFF
  • pro-oxidant food supplements or others widely known to bring good benefit to radio/chemo will be used in a continuous manner; examples are: Omega 3, Aremisia Annua, Silver Solution.

In this case, repurposed pro-oxidant drugs such as Sulfasalazine, Auranofin, etc., can be also used in cycles such as 2 weeks ON and 2 weeks OFF.

If there is no chemo/radio done/available (or e.g. Taurolidine) , I would consider the intravenous treatments mentioned in the figure above, as the core treatment, i.e. Vitamin C + EDTA, Artesunate, 2DG, and build the strategy around them. In that case, I would probably go with these 2x/week supported by the “reduce anti-oxidant category” and do such a cycle for 3-4 weeks (followed by a 2 weeks off, to reduce the oxidant pressure on the body). The intravenous treatment would be done in the following way in my view: First High Dose Vitamin C+EDTA, followed by 2DG metromic (if possible), followed by Artesunate.

High dose Vitamin C are suggested to be given in combo with EDTA since this combination triggers an increased pro-oxidant effect (Ref.). This seems to be related to the fact that EDTA increases the intracellular labile iron pool (LIP) with exogenous Fe2+, that in turn increases the pro-oxidant effect of high dose Vitamin C (Ref.). Most of the private cancer clinics have available EDTA intravenous. If EDTA is used, I would first start with a lower dose of Vitamin C compared to that used when Vitamin C alone is used.

This strategy will likely induce cancer cell death via ferroptosis too (Ref.) as ROS-mediated autophagy increases intracellular iron levels (Ref.). Since ferroptosis is an autophagic cell death process, it is best not to use HydroxyChloroquine while on this strategy (Ref.). I would rely more on ferroptosis in case chemo or radio is not used. If chemo or radio is used, I would rely less on ferroptosis and I would use HydroxyChloroquine due to it’s additional value to chemo as an autophagy inhibitor.

In parallel to the treatment, I would have an eye on the diet, and specifically try to reduce the intake of glucose (sugar), glutamine (red meat) and Methionine (found in meat, fish, and dairy products). This is because glucose becomes a good fuel for NADPH production, Glutamine a good source for Glutamate production, and Methionine is converted in Cysteine inside the cells. Of these, Methionine-free diet could be the easiest to achieve and most relevant for this strategy. Here are a few relevant studies on Methionine-free diet:

Extending the “Pro-Oxidant Strategy” Strategy

If I would want to increase the strength of the “Pro-Oxidant strategy” my first step would be to focus on the strategy “Cellular Building Blocks” inhibition and more specifically, I would do my best to inhibit the Melavonate Pathway.

By doing that, there is a good chance to inhibit glutathione peroxidase (GPx) which is the first line of defence of cells against hydrogen peroxide.

“Cellular Building Blocks” inhibition and inhibition of the the Melavonate Pathway

Inhibition of Melavonate Pathway has been discussed on this website extensively here and here. The following are the major inhibitors I would use:

  • HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
  • Atorvastatin typically used in cancer treatments in a dose of 40-80mg/day
  • Dipyridamole typically used in the range of 200mg 2x/day
  • Lycopene typically used in a 100mg/day range

Shut Down Energy Engines

If there is space for more, I would strongly consider adding the “Shut Down Energy Engines” and I would specifically focus on the fermentation inhibitors. Of those, the best that would fit here would be 3BP (3-Bromopyruvate), because it increases ROS directly next to inhibiting fermentation.

Out of “Shut Down Energy Engines” I would only pick the fermentation inhibitors (and not mitochondria inhibitors) because, when there is too much ROS produced by mitochondria (due to high energy demands) malignant cells start adopting a fermentation-based (glycolytic) metabolism that in turm reduces the mitochondrial production of ROS. So, by reducing fermentation, malignant cells have no other option than producing energy via mitochondria producing ROS that would kill them, or slow down the growth.

“Nutrient depletion”

Furthermore, I would consider the use of PhenylButyrate (typically used in the range of a few g/day) as a Glutamine depletor. PhenylButyrate is only one component out of many drugs and supplements that are part of the “Nutrient depletion” strategy (that I will discuss in details in another post), but an important one to work in synergy with the strategy discussed in this post, i.e. Pro-Oxidant Strategy, due to it’s contribution to the generation of anti-oxidants in cancer cells..

Finally, I should stress that this strategy should only be used temporarily since long term anti-oxidant depletion is expected to be at the base of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease (Ref.).

Some Extra Details

The Yin: Reactive Oxygen Species

Reactive oxygen species (ROS) are a set of highly reactive molecules comprising:

  • Free radicals
    • Superoxide anion (O2−)
    • Hydroxyl radical (OH)
  • Non-radical species
    • Hydrogen peroxide (H2O2)
    • Singlet oxygen (1O2)

ROS continuously escape from the mitochondrial respiratory chain. At high concentrations they are able to react with many cellular components, such as nucleic acids, proteins and lipids, causing DNA damage that escapes the DNA repair system (Ref.). Reactive nitrogen species (RNS) are another family of free radicals, derived from nitric oxide (NO) and superoxide anion (O2−), that, acting together with ROS, can damage cells.

Mitochondria is the largest contributors of ROS in mammalian cells, converting approximately 1% of their consumed oxygen to superoxide anion (O2−) (Ref.). This happens due to a leakage of electrons to oxygen that produces ROS such as superoxide anion (O2−) and hydrogen peroxide (H2O2). There are at least 11 sites in mitochondria where superoxide anion (O2−) and hydrogen peroxide (H2O2) generation takes place (Ref.). Mitochondrial complexes I and III, are conventionally recognised as the major sites of mitochondrial production of (O2−) and (H2O2).

The Yang: The antioxidant defence of Cells

Cells have an antioxidant system to control ROS levels in cell organelles, cytoplasm and even in the extracellular space. Here are the major antioxidants or anti-oxidant systems present in the cells:

Enzymatic antioxidants or antioxidant systems:

  • Superoxide Dismutase (SOD) – an enzyme that catalyzes the dismutation (or partitioning) of the superoxide (O2−) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H2O2). Represents a very important antioxidant defense against oxidative stress in the body. It is a metalloenzyme which utilizes the metal ions including copper, iron, manganese, and zinc as cofactors to catalyze the dismutation of (O2−).
  • Catalase – enzyme that catalyzes the decomposition of hydrogen peroxide (H2O2) to water (H2O) and oxygen (O2).
  • Glutathione (GSH) system – Glutathione (GSH) is normally produced via a two-step reaction. In the first step, γ -glutamylcysteine is the product of a reaction between cysteine and glutamate (from Glutamine) enabled by the enzyme glutamate cysteine ligase (GCL). Glycine is then added to produce GSH through glutathione synthetase. GCL activity and cysteine levels, but not glutamate or glycine, are the rate-limiting substrate because intracellular concentrations of both glutamate and glycine are higher (Ref.) GCL is inhibited by inhibited by buthionine sulfoximine. Glutathione is also cosubstrate for glutathione peroxidases (GPX) which are part of the cellular enzymatic antioxidant network responsible for scavenging organic and inorganic peroxides, creating the GSSG oxidised form. Another enzyme part of this system is Glutathione S-transferases (GST) catalysing the conjugation of electrophilic substrates to glutathione (Ref.)
  • Thioredoxin (Trx) system – One of the major antioxidant systems that maintains the intracellular redox homeostasis is the thioredoxin (Trx) system. Consists out of  thioredoxin (Trx), thioredoxin reductase (TrxR) enzyme, and nicotinamide adenine dinucleotide phosphate (NADPH), all of which as one maintains cellular redox balance by directly inhibiting ROS (Ref.).
  • Peroxiredoxins –  cysteine-dependent peroxidase enzymes that play dominant roles in regulating peroxide levels within cells. These enzymes, often present at high levels and capable of rapidly clearing peroxides (Ref.)
  • Heme oxygenase-1 (HO-1) protein – antioxidant mechanism of Heme oxygenase-1 involves an increase in Superoxide Dismutase and Catalase (Ref.)

Example of non-enzymatic antioxidants (found as food supplements):

  • Vitamins E and A
  • Alpha Lipoic Acid (ALA)
  • N-acetyl cysteine (NAC)
  • Coenzyme Q
  • NADPH
  • Glutathione (GSH)
  • Uric Acid
  • Albumin
  • Bilirubin

As discussed above, the anti-oxidant level inside the cells is controlled by Nrf2, that is a global regulator of the oxidative stress response.

Many of the above anti-oxidants can be found as food supplements at online shops. That includes, Superoxide Dismutase (SOD), Glutathione (GSH), Catalase, Alpha Lipoic Acid (ALA), N-acetyl cysteine (NAC), Vitamins E and A. It makes sense to have some of these at home to address potential side effects of chemo or radio whenever those side effects are not manageable otherwise.

Bellow, is a figure to give you a feeling on how ROS are addressed by various anti-oxidants.

References

Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin and Glutathione Dependent Metabolism https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077643/

The current study determined if depletion of glutathione (GSH) and inhibition of thioredoxin reductase (TR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol dependent oxidative stress. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc- cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2AAPA, a GSH-reductase inhibitor, were used to inhibit GSH- and thioredoxin (Trx)-metabolism. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44+CD24-ESA+ or ALDH1), and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations. Combined inhibition of GSH and Trx-metabolism enhanced cancer cell clonogenic killing and radiation responses in human breast and pancreatic cancer cells via a mechanism that could be inhibited by N-acetylcysteine (NAC). Au, BSO, and radiation also significantly decreased breast cancer cell migration and invasion in a thiol dependent fashion that could be inhibited by NAC. In addition pre-treating cells with Au sensitized breast cancer stem cell populations to radiation in vitro as determined by CD44+CD24-ESA+ or ALDH1. Combined administration of Au and BSO, given prior to radiation significantly increased the survival of mice with human breast cancer xenografts as well as decreasing the number of ALDH1 positive cancer stem cells. These results indicate that combined inhibition of GSH- and Trx-dependent thiol metabolism using pharmacologically relevant agents can enhance responses of human breast cancer stem cells to radiation both in vitro and in vivo.

Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641882/

Metabolic Regulation of Redox Balance in Cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678865/

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis.

Role of Nrf2 in Oxidative Stress and Toxicity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680839/

Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body’s needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol–based redox signaling. The nuclear factor erythroid 2–related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.

Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development https://www.hindawi.com/journals/omcl/2019/9372182/

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.

Potential Applications of NRF2 Inhibitors in Cancer Therapy 

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

Pro-oxidant natural products as anticancer agents https://www.ncbi.nlm.nih.gov/pubmed/22594470

Cancer cells produce high levels of reactive oxygen species (ROS) that lead to a state of increased basal oxidative stress. Since this state of oxidative stress makes cancer cells vulnerable to agents that further augment ROS levels, the use of pro-oxidant agents is emerging as an exciting strategy to selectively target tumor cells. Natural products have provided a significant contribution to the development of several drugs currently used in cancer chemotherapy. Although many natural products are known to affect the redox state of the cell, most studies on these compounds have focused on their antioxidant activity instead of on their pro-oxidant properties. This article provides an overview of natural products with pro-oxidant and anticancer activities, with special focus on plant secondary metabolites, and discusses their possible use as cancer chemotherapeutic agents.

Mitochondrial electron transport chain, ROS generation and uncoupling https://www.spandidos-publications.com/10.3892/ijmm.2019.4188

The mammalian mitochondrial electron transport chain (ETC) includes complexes I‑IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I‑IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiological and pathological regulation of ROS. As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a number of diseases are closely related to ROS overproduction. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1‑5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temperature in a cold environment through non‑shivering thermogenesis. The core role of UCP2‑5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are associated with UCPs.

The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562400/

The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of intracellular cysteine to support cellular processes. In contrast, many cancers require exogeneous cystine for proliferation and viability. Herein, we review how the cystine transporter, xCT, and exogenous cystine fuel cancer cell proliferation and the mechanisms that regulate xCT expression and activity. Further, we discuss the potential contribution of additional sources of cysteine to the cysteine pool and what is known about the essentiality of these processes in cancer cells. Finally, we discuss whether cyst(e)ine dependency and associated metabolic alterations represent therapeutically targetable metabolic vulnerabilities.

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724225/#B43-nutrients-11-01926

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer.

Inhibition of cancer antioxidant defense by natural compounds https://www.oncotarget.com/article/13723/text/

All classic, non-surgical anticancer approaches like chemotherapy, radiotherapy or photodynamic therapy kill cancer cells by inducing severe oxidative stress. Even tough chemo- and radiotherapy are still a gold standard in cancer treatment, the identification of non-toxic compounds that enhance their selectivity, would allow for lowering their doses, reduce side effects and risk of second cancers. Many natural products have the ability to sensitize cancer cells to oxidative stress induced by chemo- and radiotherapy by limiting antioxidant capacity of cancer cells. Blocking antioxidant defense in tumors decreases their ability to balance oxidative insult and results in cell death. Though one should bear in mind that the same natural compound often exerts both anti-oxidant and pro-oxidant properties, depending on concentration used, cell type, exposure time and environmental conditions. Here we present a comprehensive overview of natural products that inhibit major antioxidant defense mechanisms in cancer cells and discuss their potential in clinical application.

On the Inhibition Mechanism of Glutathione Transferase P1 by Piperlongumine. Insight From Theory https://www.frontiersin.org/articles/10.3389/fchem.2018.00606/full

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745761/

Potential Anticancer Activity of Auranofin https://www.jstage.jst.go.jp/article/cpb/67/3/67_c18-00767/_html/-char/ja

Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438930/

Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.

Phase I Trial of High Dose Paracetamol and Carmustine in Patients With Metastatic Melanoma https://pubmed.ncbi.nlm.nih.gov/12690304/

Reduced glutathione (GSH) production by tumour cells has been proposed as a mechanism for resistance to alkylating agents. High levels of paracetamol can deplete intracellular GSH. We conducted a phase I trial of high dose paracetamol and carmustine (BCNU) in patients with advanced malignant melanoma to determine the optimal biological dose and the maximum tolerated dose (MTD) with the goal of increasing sensitivity to BCNU by GSH depletion. Groups of three to five patients received escalating doses of paracetamol (10, 15 or 20 g/m(2)) every 3 weeks. Every other cycle, BCNU (10 mg/m(2)) was given 6.5 h after administration of paracetamol and 45 min before a 20 h infusion of N-acetylcysteine. Once the MTD for paracetamol had been determined, the dose of BCNU was sequentially escalated in subsequent cohorts to 150 mg/m(2). GSH levels were measured in peripheral blood mononuclear cells (PBMCs) and, when available, in tumour biopsies. The MTD of paracetamol was 15 g/m(2). The dose of BCNU was safely escalated to 150 mg/m(2). The most common toxicity was grade II nausea/vomiting. At 15 g/m(2), peak paracetamol levels (median 253 microg/ml) were reached between 1 and 4 h. No changes in GSH levels in PBMCs were seen. There were two partial responses, including a dramatic decrease in hepatic metastases. Treatment of melanoma patients with paracetamol (15 g/m(2)) every 3 weeks and BCNU (150 mg/m(2)) every 6 weeks is safe. The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU.

Ferroptosis and Its Potential Role in Human Diseases https://www.frontiersin.org/articles/10.3389/fphar.2020.00239/full

Ferroptosis is a novel regulated cell death pattern discovered when studying the mechanism of erastin-killing RAS mutant tumor cells in 2012. It is an iron-dependent programmed cell death pathway mainly caused by an increased redox imbalance but with distinct biological and morphology characteristics when compared to other known cell death patterns. Ferroptosis is associated with various diseases including acute kidney injury, cancer, and cardiovascular, neurodegenerative, and hepatic diseases. Moreover, activation or inhibition of ferroptosis using a variety of ferroptosis initiators and inhibitors can modulate disease progression in animal models. In this review, we provide a comprehensive analysis of the characteristics of ferroptosis, its initiators and inhibitors, and the potential role of its main metabolic pathways in the treatment and prevention of various diseased states. We end the review with the current knowledge gaps in this area to provide direction for future research on ferroptosis.

The Hallmarks of Ferroptosis http://www.columbia.edu/cu/biology/StockwellLab/index/publications/Dixon_ARC_2018.pdf

Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redoxactive iron, and oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS/MAPK signaling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can modulate susceptibility to ferroptosis. Ferroptosis sensitivity is also governed by p53 and KEAP1/NRF2 activity, linking ferroptosis to the function of key tumor suppressor pathways. Together these findings highlight the role of ferroptosis as an emerging concept in cancer biology and an attractive target for precision cancer medicine discovery.

Ferroptosis: past, present and future https://www.nature.com/articles/s41419-020-2298-2

Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1)

The Glutathione System: A New Drug Target in Neuroimmune Disorders https://pubmed.ncbi.nlm.nih.gov/24752591/

Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.

The role of peroxiredoxins in cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351761/

Peroxiredoxins (PRDXs) are a ubiquitously expressed family of small (22–27 kDa) non-seleno peroxidases that catalyze the peroxide reduction of H2O2, organic hydroperoxides and peroxynitrite. They are highly involved in the control of various physiological functions, including cell growth, differentiation, apoptosis, embryonic development, lipid metabolism, the immune response, as well as cellular homeostasis. Although the protective role of PRDXs in cardiovascular and neurological diseases is well established, their role in cancer remains controversial. Increasing evidence suggests the involvement of PRDXs in carcinogenesis and in the development of drug resistance. Numerous types of cancer cells, in fact, are characterized by an increase in reactive oxygen species (ROS) production, and often exhibit an altered redox environment compared with normal cells. The present review focuses on the complex association between oxidant balance and cancer, and it provides a brief account of the involvement of PRDXs in tumorigenesis and in the development of chemoresistance.

Redox and Metabolic Circuits in Cancer https://www.frontiersin.org/research-topics/6407/redox-and-metabolic-circuits-in-cancer

Novel Insights Into Redox System and the Mechanism of Redox Regulation https://pubmed.ncbi.nlm.nih.gov/27255468/

In view of the critical role of redox system in numerous physiological and pathophysiological processes, it is important to clearly understand the family members and regulatory mechanism of redox system. In this work, we will systematically review the current data detailing the reactive oxygen species (ROS), enzymatic and non-enzymatic antioxidants and redox sensitive transcription factors and we give a brief description of redox-mediated epigenetic and post-translational regulation. We propose that the redox system functions as a “Redox Chain”, consisting of “ROS-generating Enzyme Chain”, “Combined Antioxidant Chain” and “Transcription Factor Chain”. We suggest that an individualized assessment of the redox status in the body should be conducted for the redox intervention of a patient. The strategy of intervention is to maintain redox homeostasis via either facilitation of ROS signaling or enhancement of antioxidant defense. These findings provide valuable new insights into redox system and open up new paths for the control of redox-related disorders.

Cross-talk Between Two Antioxidants, Thioredoxin Reductase and Heme oxygenase-1, and Therapeutic Implications for Multiple Myeloma https://pubmed.ncbi.nlm.nih.gov/26795735/

Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients.

Mitochondrial Calcium Regulation of Redox Signaling in Cancer https://pubmed.ncbi.nlm.nih.gov/32059571/

Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.

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62 thoughts on “Modulating the Yin and Yang Energy of Cells to Fight Cancer: Pro-Oxidant Strategy

  1. Someone above asked for the best source of retinoic acid. The best natural sources are cod liver oil and liver (organic calf liver is best). http://www.lymphomasurvival.com has the references for these. The cod liver oil in addition has the all-important omega 3’s to fight inflammation. I take 3 Tbsp or more of cod liver oil a day.

    As a side note, I started chemo in January 2020 (R-CHOP) for Stage IV follicular lymphoma, relapsed and partly aggressive. I do and take many things, many discussed on your wonderful website! Like DCA, ozone, mistletoe injections, LDN, metformin, some other repurposed meds like etodolac, loratidine, many supplements, low carb diet, etc. Many of my strategies I get from “How to Starve Cancer” by Jane Mclelland and also your website. I also started fenbendazole (250 mg 3 days a week, 4 days off) the same time as chemo. Per Joe Tippins protocol And…I fasted 2 days before and the day of chemo to put my normal cells into hibernation mode and leave the cancer cells out there. I did a “fasting mimicking” per Valter Longo’s research and protocol on fasting and cancer but I use a modified lower carb, bit higher protein, and bit higher fat. And also drank a lot of bulletproof coffee the day of chemo to open up circulation.
    After 2 cycles of chemo (which were very hard on me), the cancer was 90% gone! This is a very excellent and atypical response. One of my doctors thinks it’s due to the fasting. I wonder also about the fenbendazole.
    I also re-negotiated the dose of the chemo with my oncologist, to reduce the steroids, and drop out one of the very problematic drugs. I live in Sacramento California. Please know that you can negotiate your own treatment!!! I know too much not too since I am a nutritionist, health educator, and do much research, as all of you do.
    Daniel I wanted to say that I gave your website to my functional medicine doc (Dr. Eric Hassid at Sutter Sacramento Integrative) who thinks you and your website are absolutely brilliant! He knows a lot about cancer metabolics and is learning more from me. I gave him your “Shutting Down the Powerhouse of Cancer” article. He’s starting a study of Glutathione and IV Vitamin C and will have his own IV room soon. Hes really into glutathione, but I am not so much.
    Daniel and everyone, thank you for all you do!

    1. Dear Adele,

      It’s so nice to hear that your treatments are successful. And this is no wonder since from your message I understand you are doing your homework very well and take the best from every one. Thank you so much for sharing your positive experience and the drugs and supplements you used as this well help others! And thank you for letting me know on the feedback from Dr. Eric Hassid. That is very nice to hear!

      Kind regards,
      Daniel

  2. Dear Daniel,

    Thank you again for such an accurate and well structured article. Possible actions are well defined and that is a great help in defining a strategy. It is just what I was looking for since I am going to start with taurolidine shortly! I’m going to select the lightest drugs for the liver. The mevalonate route with HCA, atorvastatin, lycopene and sodium phenylbutyrate is very relevant.
    It was not clear to me whether to use hydroxychloroquine with salinomycin (as I usually do).
    I will present my personal cocktail shortly, I have to take into account the possible hapatotoxicity.
    I admire you Daniel, thanks again!

    1. Hi Manuel,

      I just wanted to answer your e-mail and let you know that I wrote this one with you in mind! But you were faster than me adding a comment here 🙂
      I hope this helps and answers some questions, and yes, please let me know when you like to discuss the strategy you put in place. And thank you for being so kind!

      Kind regards,
      Daniel

      1. The feedback loop on this blog is producing wonderful results! And I like the name of the supplements company, MCS Formulas, you’re doing fantastic work, Daniel!

        1. Thank you so much Johan!

          We should be able to do so much more in the coming years, and after we get some momentum I hope you will be able to join so that we can work on both the products but also contribute to the oncology projects that will be supported by MCS Formulas. Btw, is there any great work done around the world that comes in to your mind that you think we should really support? I am thinking of three projects to start with:
          1. cell acidifiers
          2. glycolsis inhibitors (2DG metronomic)
          3. ???
          (For both number 1 and 2 I have very good scientists and clinicians in mind that can collaborate towards not only study but also implementation.)
          Of course, if you have more ideas (or other people reading this) it would be a pleasure to discuss and decide. Thank you.

          Kind regards,
          Daniel

          1. You can count on me! Something interesting would be “improve what we already have.” New reformulations …. mitho formulations, nano formulations, peptides, liposomes, pegylated liposomes and new ways of delivering compounds. we could work a lot in these fields and they can be a game changer. I know universities interested in carrying out joint research projects …
            In general, we Spanish speak poorly English …. (I promise talks at a language academy haha)

            1. Hi @Manuone

              Can I contact with you by email? I’m from Spain I’d like to be in contact with you.

              Thank you

              Inaki

            2. Hi Inabari,
              Of course, I will be happy to contact you! you can ask Daniel for my email

              kind regards

  3. Daniel, this is definitely the right direction. I do however question the mechanism around anti-oxidants rescuing the tumor. This is a common theory that is generally given by practioners to not use IV vitamin C (IVC has both pro-oxidation effects, from the fenton reaction, as well as it’s inherent anti-oxidation effects). As you mention many chemo drugs work through pro-oxidation and I posit that even after the infusion has stopped there is usually a fair amount of residual chemo in the system … this continues to work against the tumor for some time (up to 6 hours I believe). I theorize that what is happening when this “rescue” effect is observed is due to the anti-oxidants reducing those residual chemo agents thereby making them harmless and allowing the tumor to rescue itself, not that the tumor itself benefits in some way from the anti-oxidant. Other than the scenario you suggest wherein the tumor was subjected to an oxidizing chemo agent, as anyone ever demonstrated in vitro or in vivo case where subjecting a tumor to anti-oxidants have caused it to grow?

    Regardless, for this reason (the inactivation of residual oxidizing chemo) most oncologists who use IVC wait a minimum of 6 hours between the conventional chemo and IVC protocols (and generally this is accommodated by doing them on different days). I should also note that at least for vitamin C the number of anticancer mechanisms are manifold, I’ve counted at least a dozen, although over half of those are related to the expression of H2O2. The point being that even in the absence of a pro-oxidatation effect (generally observed when blood ascorbates exceed 1mmol/L) a number of anti-cancer effects are still in play so again it seems unlikely that the IVC is rescuing the tumor as much as it could inactivate (ie. reduce) the oxidation effects of the residual conventional chemo.

    Still, on rare occasions (patient specific) even IVC has seemed to result in a proliferation of cancer. This has led me to the inevitable conclusion that precision oncology is the future, but precision oncology using the selective agents that you have mentioned. Nobody is doing that, and it is clearly the right step forward. It involves culturing the tumor (this is already done in some immunology treatments), then testing the culture against a battery of the agents you discuss herein. If a single test could be developed to test all these substances against a single culture in one step … well there you’ve both cured cancer for everyone and developed a product that will fund your operation into perpetuity.

    1. Dear Lullabyman,

      Very nice to hear from you again.
      First, I should clarify that I believe fighting cancer with both pro-oxidant and anti-oxidant approaches can lead to successful results. My point with these strategies is that we need to be consistent with our choices and not mix things up. If we chose to fight cancer with pro-oxidants we should make sure we increase the chance of success by avoiding strong-antioxidants at the same time, and instead using some of the drugs and supplements addressed in this post.

      Also, I want to be clear again that plant extracts such as Curcumin, EGCG, etc. can act as pro-oxidants at cellular level, in humans. And I mentioned some of the related mechanisms in the post above.

      In general I do agree with you in that I do not see anti-oxidants as fuelling tumours. In normal conditions (e.g. not during chemo/radio) I see anti-oxidants as possibly helping cancer cells deal with higher ROS amount (negative action – cancer cells may benefit from this) and at the same time helping the body and the extracellular tumor space getting ROS away (positive action – reducing the chance for the tumour to grow). Nevertheless, I think there are more positive points than negative behind anti-oxidants since the anti-oxidants action comes with more than anti-ROS mechanisms. Therefore, I think in normal conditions anti-oxidants are a good choice specifically if they come from food and supplements.

      The story changes however, when a patient receives chemo/radio or other pro-oxidant therapies. And this is the reason for this post. The ROS triggered by chemo, radio, 3BP, and others stays in the system at least 3 days based on direct experience (as mention in this post and several times in other comments). The ROS is putting the pressure on cancer cells even days after the chemical is out of the blood. And that is the moment when I would not use strong anti-oxidants like ALA, NAC, GSH, etc. Only that time I am worries if someone adds strong-antioxidants, since those will cancel out the effect of ROS inside tumors.

      As you know, with IVC we need to clarify if it is high dose or low dose. If it is high dose I would not be worried to start applying it even after 6 hours. However, the low dose IVC should go away from that point and start only 2-3 days latter. There is only one reason why I could still see a potential bennefit in IVC low dose so fast after chemo and that is it’s anti-inflammatory action. But if we want to achieve that, which is a good idea, I would better use metronomic 2DG instead of metronomic IVC, 6 hours after chemo/radio. Again, we are discussing here about specific cases – otherwise I like Vitamin C regardless if is high or low dose.

      Indeed, testing tumours against such agents could be very relevant. And being able to do that from time to time could be even more relevant as tumours will tend to change their profile. Btw, this is an interesting tool to study tumours https://www.nanostring.com/products/ncounter-systems-overview/ncounter-overview-system-selection-guide but the price is somewhere on the range of 200k.

      Kind regards,
      Daniel

      1. Okay, yes 3 days rather than 6 hours … I’m sure that some substances flush out faster than others. So yeah, I do agree with your proposed protocol to hold off on the more aggressive anti-oxidants in that time frame. In fact this is what I recommended in the following document I provided in the IVCbook: https://tinyurl.com/ve9jcmj You’ll observe in the gray writing about each table “IVC-days: The Cancer-Selective Pro-oxidation Strategy” for the Pro-oxidation guidelines, and “The Strong-Fighter Strategy” to be employed on the days when anti-oxidation is recommended. You’ll not that one of the things I tell the patient to avoid during pro-oxidation is “Antioxidants not yet proven synergistic”. Having the patient be aware of what they can do food wise and supplement wise is important so that they don’t inadvertently sabotage the pro-oxidation strategy. I will tell you that this is a hard thing to get naturopathics to agree to. The idea that you avoid certain anti-oxidating supplements is a tough one for them to swallow, even after you explain the sound reasoning for it.

    2. Very very interested in your answer because I had bad results with IVVitC.
      Only oxidation has ever worked in my case.
      So Thank you (I wrote some posts these last days below the article about IVVitaminC. I knew that someone had reserves about VitC and I least, I read this post again !).
      https://www.cancertreatmentsresearch.com/high-dose-vitamin-c-cancer/#comment-11270
      https://www.cancertreatmentsresearch.com/high-dose-vitamin-c-cancer/#comment-11272

  4. Something for thought … in working out this strategy with another researcher (Dr Hunninghake, Chief Scientist at the Riordan Clinic) I developed an acronym that is really up for grabs for anyone who wants to use it. It is SuCCeED, Sustained Cancer Cell Energy Depletion. So that any protocol used to rob a cancer cell of it’s energy is a SuCCeED Protocol. Alternatively SUCCeED, Selective Unabated Cancer Cell Energy Depletion. Regardless, a key feature of any protocol used to starve cancer of it’s energy supply must be sustained, ie. unabated … I fear that with the strategy you suggest here one of the key challenges, and why it sometimes fails, is precisely because it isn’t done for long enough. Albeit, that can be hard to do. For example, if the mechanism is to monopolize all the glut transporter sites it can result in a bit of an energy crisis for the normal cells as well as the cancer, so that the patient experiences hypoglycemic side effects. Although IVC (for example) has few side effects, this is one of them for many patients when the dose is very high and extended. Some doctors have even been know to try and compensate by providing them with sugary drinks! (which of course rescues all the cancer cells)

    1. I think the SuCCeED idea applies better for this strategy https://www.cancertreatmentsresearch.com/shutting-down-the-power-house-of-cancer/
      I agree that any strategy should be applied for long enough time in order to work. But I think, applying a strategy that is consistent for 5-7 days from time to time while in between these pulses focusing on the good health of the body could be very effective. Nevertheless, the point of the strategy above is to increase the effectiveness of pro-oxidant therapies.

      Kind regards,
      Daniel

      1. Yeah, that is a better fit. The relationship with pro-oxidation is that H2O2 does cause NAD-depletion (in addition to plugging up the glut transporters) which causes an energy crisis in the cancer cell. Of course these are closely related … the advantage of the pro-oxidation of course being a direct attack on the cancer cell. I’ve also concluded that merely shutting down the energy source for cancer is not enough when these little buggers are designed to go dormant in that scenario, just waiting to be revived when the power source is back on line.

  5. Wow wonderful info Daniel, Thank you very much

    I´m a little surprised to see high egcc extract and curcumin before and during days with oxidative protocols as radio, artemisinin,… Is this possible because by oral route the antioxidant effect is low to cancel ROS process?Or is because at that dosages reduces the body antioxidants?

    It´s also a pity to be so hard to find Auranofin available , i have tried to buy it but no luck for the moment.

    Very good nes with the supplement company too, i wish we can buy them from Spain.

    Kind regards

    Inaki

    1. HI Inaki,

      Thank you for your comment. This is a very fair point you made regarding Curcumin, EGCG.
      It is clear that the more we study the more we learn. Curcumin and EGCG come back in some many anti cancer mechanism … even here in the pro-oxidant strategy where normally we would not expect them. But here they are, based on science. Actually, I was discussing some weeks ago with one of the very good doctors and scientists allocate his life to oncology for >20 years and he has exactly the same view after studying the field for so long time, the true anti-oxidants and the so called anti-oxidants. I hope I will convince him to write an article on this subject soon and I will publish here. Nevertheless, this is what I came up with after doing the study. If we feel that we should put Curcumin and EGCG a few days away from chemo, we can still do that if it makes us more comfortable. As you can see, although science would indicate that we can use them, I did not put them in the first line category but in “other options” exactly because of this reason.

      Regarding the supplement company, we should be able to deliver world wide (including Spain) and 50% of profits will be invested back in the company to grow, and 50% will be given to projects (academic and clinical) to address exactly the points we are discussing here. It will be so nice when we can do that.

      Kind regards,
      Daniel

  6. Hi Daniel

    Thank you very much for this article. It is a good add-on to the another article about Increasing chemotherapy efficiency.

    BTW, what do you think of adding ozone therapy and electroporation to the list of pro-oxidants (when/whereever it is possible)?
    https://www.ncbi.nlm.nih.gov/pubmed/10556494
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459148/
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632793/

    I don’t know if drinking ozonated water makes it bioavailable right at the tumor site, but in case if it is – that will be much cheaper alternative to difficult to find pro-oxidant drugs (e.g. auranofin).

    For silver np, iv application is mentioned, though Silver Bullet article doesn’t mention IV dose and application details.
    Is IV silver np treatment practiced somewhere, and are there articles to read about it?
    Appreciate if you can elaborate on this.

    Thank you and Kind Regards

    Asaf

    1. Hi Asaf,

      I think this is a very good idea indeed. I actually wanted to add ozone but forgot about hat although I had this article open which I find very nice https://drrowendrsu.com/wp-content/uploads/2020/03/A-Plausible-Penny-Costing-Effective-Treatment-for-Corona-Virus-Ozone-Therapy.pdf
      According to the included references in this article, you could argue that the strategy discussed above (and many of the discussed drugs, specifically Sulfasalazine) should be also effective against corona virus since it requires Cysteine.

      Actually ….. that reminds me about hydrogen peroxide which is another option that sometimes is used even intravenous – I will have to look back to my notes on that since many years ago, but I should add it here too since it’s very relevant.

      I did not discussed silver as intravenous in the article above – only as an oral version – of course some clinics do that also intravenous. I remember there was a clinic in Greece doing the IV but I am not sure if I can find back the name of the clinic. If I find I will let you know. I think there was one even in Turkey …. at least Ergin was discussing about that I think, some years ago – I will check that too. Many things to do 🙂

      Thanks for your very valuable additions. I will integrate them.

      Kind regards,
      Daniel

      1. Hi Daniel

        Thank you very much for explanations.

        What do you think of possible co-administration of chemo or radio therapies (first) and ozone (right after) as we have ozone therapy facility on walking distance from our apartment?

        Thank you

        Asaf

      2. Hi Daniel

        Regarding silver -appreciate if you could share your opinion on its co-administration within various strategies/protocols posted in this site.

        Thank you

          1. Hi Daniel

            I have read this article of course.
            Available literature for silver np claims its pro and anti oxidant activity at same time, similar to some other natural supplements. As for every drug, my question was about when (timing) to use it, what is the best combination with other drugs, to get either additive or synergistic results, and avoid possible antagonism … from practical experience point of view.
            I would love to go with trial and error method, but there is not much room for it in my case.

            Kind Regards

      1. Great contribution Daniel! DCA + metformin combination increases dichloroacetate efficacy through exacerbation of oxidative stress !. I should use it cautiously because I suspect that my mother is not feeling well when she was taking DCA.

        Daniel did you see my new cocktail in the forum? I will greatly appreciate your opinion when you are not busy

  7. Hello, Daniel, whaou !!!! What a wonderful article, so exhaustive. Bravo !

    I think it’s one of the most important question regarding cancer’s treatment : chose the strategy, oxidant or anti-oxidant. People shows successes with each one.
    – Hum, hum, do you think it can depends also on the type of cancer ?

    – About curcumin which becomes oxidizing when administered in high doses, I read your article and discussion with Ovidiu in the posts ; I also found these informations which go on the same direction :
    https://www2.fcfar.unesp.br/Home/ComitedeEtica/CEPHumanos/28_2011_artigo1.PDF
    Indeed, it is complex :
    https://www.researchgate.net/post/Curcumin_is_an_antioxidant_or_a_ROS_producer

    Last post in the link below seems very interesting, depends on temperature and cancer’s cells have higher temperature than healthy cells.
    Reference

    – You explained on your article on Vitamin C that it becomes oxidant at high doses.

    -> Please, may I ask you what do you think of melatonin high dose ? 180 mg/ a day, even more. Here (first link), in a video of the Riordan Clinic that you probably know, a doctor who has great successes with it says melatonin is antioxidant and effective with all chemos. But I can’t help thinking it becomes oxidant when high doses (second link),or he uses high doses. However, I have conversion difficulties and I just suppose 180 mg is a high dose, without being absolutely sure.
    I would appreciate having your opinion about melatonin (and its doses).
    https://www.youtube.com/watch?v=Roh4lQXneQg&feature=share&fbclid=IwAR3B9nBQy1BzOglSsYGmSq__fZFWpaI6aHbQl-z-kgRbzK9rkhk2LPBBvys

    https://www.ncbi.nlm.nih.gov/pubmed/29704993
    https://www.researchgate.net/post/did_the_higher_dose_of_melatonin_has_the_reverse_affect_on_its_antioxidant_action

    Have a nice evening !

    1. Dear Nathalie,

      Thank you for your comment and questions.

      It makes sense to think that anti-oxidant strategy would be most suitable for initial stages, while pro-oxidant strategy would be more relevant for advanced stages when more aggressive/intensive approaches are required (in general), but best to be used in pulses and not continuous because of the ROS toxicity to the whole body.

      Regarding Melatonin in high dose, I do not have an opinion on it at this point. As soon as I find time I will study this subject and share with you my opinion.

      Kind regards,
      Daniel

  8. H D- Thank you for this wonderful and well-put-together post! It is sooo helpful for me and I am sure for many others. Once we are able to travel again we will hopefully be doing Lu-177 radioligand therapy and I was starting to think about ways to increase the efficacy, this post will be of great help. Thank you for your dedication and service to humanity.
    Warmly,
    Shanti

    1. Dear Shanti,

      Thank you so much for your kind msg and I am glad this may help!
      If I think of radiotherapy, this post would be relevant also mitochondria inhibitors also the cell acidifiers.
      Trying to activate the immune system prior to that with various supplements and using alaklizing agents should help.
      Myo-InositolTrisPyroPhosphate (ITPP) (and or Niacin and or coffee) and may also be interesting prior to radio to enable better oxygenation.

      Kin dregards,
      Daniel

      1. Hi D-
        Thank you for the additional tips! All of them make sense to increase stress on the cancer cells, help the immune system react to cancer as it becomes visible the immune system when it is killed, and increase blood flow and oxygenation to help the radiation work better.
        Warmly,
        Shanti

      2. I was looking back through this blog post and your message. There are actually quite a few things I would feel comfortable implementing to help with the Lu-177-PSMA Radioligand therapy that would not likely have any impact on PSMA expression, but hubby wants to “go clean” on the first round. He is considering fasting, however.

  9. Could copper be used as oxidative stress inducer for possible synergy with chemo?

    https://pubs.rsc.org/en/content/articlelanding/2016/dt/c5dt04842g#!divAbstract
    Doxorubicin-conjugated CuS nanoparticles for efficient synergistic therapy triggered by near-infrared light

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1660546/
    A novel copper complex induces ROS generation in doxorubicin resistant Ehrlich ascitis carcinoma cells and increases activity of antioxidant enzymes in vital organs in vivo

    https://www.ncbi.nlm.nih.gov/pubmed/15836927
    Differential profiles of copper-induced ROS generation in human neuroblastoma and astrocytoma cells.

  10. Hello Daniel and all;
    I recently stumbled across your incredible and valuable website/blog and only wish I had found it sooner! I am a cancer patient, initially inoperable Stage 3B squamous cervical cancer/HPV, after chemo/radio/Brachy, NED for 1.5 years, now recurrent. Only option suggested was palliative chemo except now they are trying immunotherapy (Keytruda) as my tumor shows 30% PD-L1. In reading this article I am coming to the conclusion that it would be wise to avoid all antioxidants to allow the immune system to do it’s job? Provided, of course, that the Keytruda is working (CT can later this month to determine). Right now I am on a vegan, low carb diet, at least 50% raw, taking many supplements (too many to list here) but some of the usual suspects: curcumin, ECGC, Vit D, Berberine, Omega 3 and 7 EFA, garcinia and a whole boatload of others. Can you provide any suggestions as to what antioxidant supplements should be avoided during immunotherapy and which others one should add? Add Polydatin for instance, been hearing a lot about that? Lipsomal Vit C (can’t afford IV C and if I could, most places that administer are closed to to Covid-19). As you can see, the majority of what I am using are natural supplements and diet. The only “off label” drugs I am using/was able to acquire is Metformin(500mg,)low dose aspirin(81mg) and Lipitor(40mg). Thanks for this wonderful resource and any direction you can provide.

    1. Dear Loretta,

      I am sorry you have to go through this challenge and I hope you will get better soon. To support immunotherapy, there are many things that can be done, but I would not be afraid of anti-oxidants. The strategy discussed in the post above fit’s mostly with radio, chemo o other pro-oxidant treatments. It’s not focused on immunotherapy.

      I was recently writing to somebody else by e-mail, some steps that can be addressed to try and support immunotherapy drugs such as Keytruda. Here are some points on that:

      So I think the best now is to think what are the ways to
      – increase the chance for effectiveness and
      – address a potential first growth (flare) triggered by immunotherapy
      – be ready to work against side effects if they occur

      In order to increase the chance of effectiveness here is what I would consider:

      1. Around the tumors the area is more acidic and this makes the immune system by less effective. Therefore, we want to make this space more alkaline. Here I discussed why this happens https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/
      At the same link I discussed various approaches that can be used to reduce the acidity around the tumors.
      However here are a few easy approaches to do that:
      – Use Basentabs food supplements that are strongly alkaline as indicate on the package https://www.amazon.com/Pascoe-Basentabs-pH-balance-200-Tabs/dp/B01ATZG6M6
      – Or you could go to a cancer clinic near you and ask them to perform Natrium Bicarbonate intravenous prior to Immunotherapy
      – Or you could use DCA as discussed here https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy
      The daily dose will be about 1g/day and it can be ordered from here https://www.dcalab.com/ or other sources.
      DCA is very bio-available so it should be no issue to be absorbed. And the same with Basentabs.
      – Taking Lanzoprazole 40mg/day taken 30 min before any meal. This is an over the counter drug in many countries.

      2. Increase the immune system activity using the following:
      – Coriolus or Agaricus Blazei 3x400mg/day or Reishi mushroom extract, 2.5g per day
      – Vitamin D3 in higher doses prior to the Keytruda IV. A suitable dose during those days would be at least 10.000ui/day
      Vitamin D3 can also be found in solution form so that is easy for you to absorb
      Mushroom liquid extracts https://www.pilzshop.de/fluessigextrakte the website is in German but you can use Google translators.
      – Atorvastatin 40mg/day increase effectiveness of immuno-therapy by activating T-cell https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313973/
      – Probiotics – one of the best probiotic is sauerkraut juice that can be made at home

      3. Reduce tumor hypoxia
      – Metformin 1g/day – Here is a clinical trial showing that Metformin may increase the effectiveness of anti PD1/PDL1 like Keytruda https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0375-1 https://www.futuremedicine.com/doi/full/10.2217/lmt-2018-0016

      In some cases, it is known that immuno therapy can trigger first a growth of the tumors and after that a reduction. In order to do try reduce that initial growth, I would consider the use of

      1. angiogenesis inhibitors, e.g.:
      – Aspirin 100mg/day – it has angio-genesis and anti inflammatory properties
      – Fenbendazole 222mg/day – has also angio-genesis inhibition properties (just follow the protocol of Joe 4day ON and 3 days OFF)
      – Silver solution – https://www.cancertreatmentsresearch.com/a-silver-bullet-to-kill-cancer/ I am not sure if you can find it in the shop as many are buying it against Coronavirus – if not, you will need to make it yourself at home as discussed in the article on my page on silver from the reference I added here

      2. anti inflammatory drugs and supplements
      – Black Cumin Oil – 1-3g/day
      – Curcumin – 3-7g/day
      – Omega 3 – 3g/day
      – Olive leaf extract – 1g/day – very strong anti-inflammation

      I would make sure I have the following at home to support the organs in case of auto-immune reactions

      – Milk Thistle – 1g/day
      – Alpha Lipoic Acid – 1-2g/day if needed
      – Quercetin 3g/day if needed

      Finally, Cimetidine could be very useful to address Tregs and MDSC. https://ecancer.org/journal/8/full/485-repurposing-drugs-in-oncology-redo-cimetidine-as-an-anti-cancer-agent.php and https://www.cancertreatmentsresearch.com/antihistamine/

      You may also want to have a look at this:
      https://www.cancertreatmentsresearch.com/anti-pd-1-and-anti-pd-l1-immunotherapies/
      and this https://www.cancertreatmentsresearch.com/gut-bacteria-amplifies-immunotherapy/

      I hope this helps.

      Kind regards,
      Daniel

      1. Oh my goodness, thanks so very much for taking the time to answer my post so thoroughly! Your response has certainly helped and given me direction. I have taken my 3rd infusion of Ketruda over the past 9 weeks and have not noticed any side effects so far. As I mentioned, I am taking a LOT of supplements and am not sure whether I need them all or should focus on others instead. It would be nice to reduce the pills to those most important. I am currently taking the following but through your webpage and others, have discovered I am not taking high enough doses of some things:
        1) Aspirin (81mg)
        2) Metformin (500mg)
        3) Atorvastatin (40mg not yet started)
        4) Quercetin (800mg)
        5) Omega 7 (Sea Buckthorn oil) (1000mg)
        6) Omega 3 (Fish Oil) (1890mg)
        7) Milk Thistle (550mg)
        8) Feverfew (400mg)
        9) Garcinia (600mg)
        10) Berberine (1200mg)
        11) Holy Basil/Tulsi (720mg) plus 1 cup tea
        12) Wobenzym N
        13) Black Seed Oil and Seeds (1 Tablespoon oil per day orally, 1 T seeds per day in food/salad)
        14) Probiotics (Dr Ohhira brand) but ordered a new/different one “ELIXA”
        15) Pomegranate and cranberry juice and capsule supplements for micro biome/akkermansia propagation
        16) L-Lysine (1000mg for suppression of HPV2)
        17) Glucosomine Sulphate (500mg)
        18) Graviola (650mg)
        19) Muscadine Grapes Extract (resversatrol etc) (550mg)
        20) Green Tea Capsules (450mg) plus 2-4 cups tea daily
        21) Bosmeric-SR (turmeric/boswellia/ginger/pepper) (1000mg)
        21) Turmeric Strength by Mega Food (1400mg) plus turmeric tea daily
        22) Cinnamon ((140mg) blood sugar/glucose control
        23) Blood Sugar Support (Mitaki, Reishi, Chago, Gymnema, Cinnamon, Bilberry)
        24) Vitamin B3/Niacinamide (550mg)
        25) Vitamin B12 (1000mcg) supplement to vegan diet
        26) Vitamin B17/Amygdalin/Laetril (100mg)
        27) Vitamin D3 (2000 iu)

        Aside from the above drugs and supplements, I am eating a very high fiber diet(for the micro biome), eating Kimchi, sauerkraut, fermented beets, coconut milk kefir, coconut milk yogurt, eating cooked mushrooms 3-4 times a week (Maitaki/Turkey Tail/Shitaki/Lions Mane/Oyster etc) but need to get a concentrated mushroom supplement as there is only a finite amount of mushrooms one person can eat!!! The only 2 fats in my diet are high quality olive oil and avocados. I eat a cruciferous vegetable every day and eat 8 ounces of fresh broccoli sprouts each week. Almost every day I drink about a quart of water with fresh lemon juice and apple cider vinegar. I have only one question: does the Olive Leaf Extract you suggested adversely affect the gut micro biome, i.e. kill the good bacteria along with the bad? I have Oregano Oil but stopped taking it as I don’t want it to kill the good bacteria I have been trying to propagate.

        From your response, I am seeing I should add to what I already take:
        • ph Acid/Alkaline Balance supplements syou uggested
        • Coriolus or Agaricus Blazei or Reishi
        • Mushroom Extracts
        • Sauerkraut Juice
        • Colloidal Silver
        • Olive Leaf Extract
        and INCREASE my dosages of Metformin, Quercetin, Curcumin, Milk Thistle, Vitamin D3 and Omega 3

        I’m not overly keen on the Fenbendazole so will skip that and as for any antihistamine type products, I can’t take them. A blood test a number of years ago revealed that I have abnormally low levels of histamine, a condition called Histapenia. The 2 times I have ever taken a antihistamine made me quite ill, blurred vision, dizziness, fatigue, sinus pain etc so I have to search for an alternative for Tregs and MDSC.
        Thanks so much for all your time, you are truly amazing!

        1. Hi Philly,

          I’d also take plenty of sulforaphane (in addition to the cruciferous veggies), there are a few good supplements on the market (BroccoMax, Avmacol®, Organic Broccoli Sprout Powder from Health Ranger etc. And of course you can get sulforaphane from fresh broccoli sprouts. Maybe take some extra magnesium to make sure you get the most out of the vitamin D supplementation. Increase Curcumin. Maybe add a little selenium (yeast bound selenium and/or sodium selenite).

          All the best,

          Johan

          1. Thanks so much Johan! Any specific brand of curcumin you recommend? It is mind boggling the number to chose from. I chose Bosmeric-SR by Sanjevani (suggested by Chris Wark) and then added Turmeric Strength by Mega Food. Now I’m looking at CurcuminRich Double Strength Theracurmin by Natural Factors. I have a cart full of items on Amazon (Lipsomal Vit C, and more and coincidentally BroccoMax!)
            Thanks again!
            Loretta

            1. One of the Curcumin I liked best was the one made by Sabinsa corporation capsule 1000mg, including Curcuminoids >95%, and BioPerine 95%. Doctor Best has it and the supplement company we start should have it soon.

              Kind regards,
              Daniel

            2. Hi Loretta,
              Here are some of the best CURC formulations IMO: BioCurc® CurcuWin® Longvida® CAVACURMIN® TetraCumin-QR(possibly best to use in combination with some of the other curcumin formulation b/c of different molecular targets) and Curcumin C3-complex® + Bioperine (like the one you’re using).
              Best,
              Johan

        2. Hi Philly,

          As Johan said, to support vitamin D, a little Mg and K2 may help.
          You are using indeed a lot of supplements and doing a lot from a diet point of view.
          Looking through your list here is my view:
          – there are many good supplements you are using
          – Quercetin I would use more or nothing – by more I mean a few g/day
          – Garcinia I would use more or nothing – by more I mean 1.5g/day
          – I have no opinion on 16) L-Lysine (1000mg for suppression of HPV2) and Glucosomine Sulphate
          – Graviola I would use more or nothing – by more I mean a few g/day
          – Green Tea Capsules more or nothing – please read this discussion https://www.cancertreatmentsresearch.com/shutting-down-the-power-house-of-cancer/#comment-10016
          – Turmeric Strength by Mega Food (1400mg) – I would make sure there is a lot of Curcuminoids inside and I would increase the dose
          – Vitamin B17/Amygdalin/Laetril (100mg) – I would not expect much at this dose so better to remove
          – Olive Leaf Extract should not interfere with good bacteria to my knowledge – I totally understand the issue with Oregano Oil which I would not use for too long time due to the reasons you mentioned

          Thank you so much for your kind words!

          Kind regards,
          Daniel

          1. Thank you so much Daniel and Johan. I have revised my Amazon cart purchases to reflect both your suggestions! Once again Daniel, your website is extraordinary, clear, concise and thorough (even my artists right brain leaning personality can comprehend it) and your dedication to the cause should be applauded. I do believe your work will save or extend lives, thank you again!

            1. Thank you do much for your kind feedback Loretta. It’s difficult for me to realise when I go too much into details and when not, and I it helps to know that is not too complex.

              Kind regards,
              Daniel

  11. Good night @daniel and everyone,

    During a pro oxidant therapy as radio, and doing a diet with wild fish daily in luch time. Is a good idea to add glycerin aminoacid with a supplement?

    I would like to know if I understand correctly to improve the ratio with methionine… Or should be better to avoid all wild fish, molusk, eggs completely?

    Kind regards

    Inaki

  12. Hi Asafh,

    Thank you for your comment. I hope you are well!

    Yes, it makes sense to add local hyperthermia on the list as well as Photodynamic therapy as they are ROS generators.

    I just want to make the point that while the strategy above fits perfectly with chemo and radio, it was not developed to specifically support chemo/radio. It can also be implemented without those.

    I do intend to discuss a strategy to support chemo, again but more in details compared to before, where next to ROS we would also address in more details various drug resistance inhibition strategies such as MDR inhibition, addressing blood vessels, anti-bacterials, DNA repair mechanisms, autophagy, etc.. In that context we can discuss in more details how we could integrate hyperthermia and others around chemo. We just have to move forward step by step and order to keep it as simple as possible, when possible.

    Kind regards,
    Daniel

    1. Hi Daniel

      I am fine. Hope you are fine too.
      Thank you for all efforts you put on this.

      It is details that makes all difference. having a strategies that could be re-scheduled and tailored will be very good. knowing boundaries and the way to change them is very important for those who are on their own to do such treatments.
      some points from patient perspective:
      auranofin has very long half-life. should that impact if cycling pro and anti antioxidant treatments will be used?
      i would love to try this with low dose radiotherapy in between heavy treatment, though don’t know whether it can generate enough ros to kill cancer cells.
      recently i came across one supplement – Pyrroloquinoline quinone (methoxatin). curious if it can be used for ros generation.
      “Pyrroloquinoline quinone induces chondrosarcoma cell apoptosis by increasing intracellular reactive oxygen species”
      https://www.spandidos-publications.com/10.3892/mmr.2018.8745
      another aspect – possibility of synergy by combination of low ros generation sources to make them potent without involvement of heavy chemo. Let say h202, silver, artemisia. is it feasible?

      Best Regards

      1. Hi Asafsh,

        Very nice to hear from you and very nice to know you are fine!

        It always depends on the specific situation, but in general I would not be worried about the long half-life of Auranofin. When pulsing, I would just remove the others and that should release a lot of the ROS pressure.

        Thank you for the link on Pyrroloquinoline quinone! The article looks good indeed. We just need to look at more of the literature behind to conclude if we can indeed add it on the list of ROS inducers. Is there more literature to support it’s action as “inhibitor of the activation of superoxide dismutase (SOD)1 and SOD2, and the formation of GSH”?

        Kind regards,
        Daniel

  13. Hey Daniel,

    Thank you for the effort and detail that you put into this site and the individual pages.

    I just wanted to hear to your take on feverfew, which you added in the diagram (as a possible / alternative mechanism) to inhibit NRF2.
    I was researching this further and it seems that feverfew can actually activate it instead of inhibiting it as we’d like in a pro-oxidation approach, correct?

    Several articles that refer to this mechanism:

    https://europepmc.org/article/med/31078744
    https://www.jdsjournal.com/article/S0923-1811%2813%2900279-X/abstract
    https://www.ncbi.nlm.nih.gov/pubmed/32257527

    Wogonin does the opposite it seems.

    1. HI Buran,

      Thank you for your comment and question. Indeed, many of the natural compounds appear to be cell type-specific, concentration-dependent, and may vary in their action depending on if we focus on cancer cells or other cells. Same applies for apigenin, luteolin in terms of Nrf2 modulation.

      Regarding feverfew, here are studies in cancer, indicating Nrf2 down-regulation activity:

      Parthenolide prevents resistance of MDA-MB231 cells to doxorubicin and mitoxantrone: the role of Nrf2. https://www.ncbi.nlm.nih.gov/pubmed/29354292
      Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis https://www.ncbi.nlm.nih.gov/pubmed/27077810
      Inhibition of cancer antioxidant defense by natural compounds https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362541/
      Potential Applications of NRF2 Inhibitors in Cancer Therapy https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6487091&blobtype=pdf

      Honokiol (from magnolia) and Wogonin (from Scutellaria baicalensis) are also discussed at the last link above, as Nrf2 modulators.

      I hope this answers your question.

      Kind regards,
      Daniel

      1. Thank you for these helpful references (and your fast reply)!

        I will check the dosage for Parthenolide /feverfew that was used in the studies references in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362541/ and https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6487091&blobtype=pdf.

        I’d assume that if there are only mouse/animal studies available, one would have to convert this to an equivalent human dose, correct? (From a quick Google search, I see that there are approaches to do this). However, if there are only ‘cell line’ studies that are available for a given a natural substance, do you know if there’s any good way to ‘guestimate’ an appropriate dose for humans (or is it even a worthwhile step to take?)

        Best wishes!

  14. Hello,

    So 0mega 3 are pro oxidant but they also have anti inflammatorie properties. I didn’t knew it was possible. It’s a good news😀.
    – What is the dosage to respect ? High level as for curcumin ?
    – Omega 3 can they be associated with statines ? Oil and anti fatty product ?

    It’s so important to check the interactions as you do, dear Daniel. Many thanks to you because you find clever strategies against cancer.

  15. Hello,

    Against me.
    Until I read this article, I believed that lycopene was antioxidant. Um, of course, I’ve seen that Grace Gosar (patient healed with statins. Alan Richardson’s protocol) had lot of tomatoes pasta to improve statins, so it was the first light.

    My question is about B17/ Amygdalin : it didn’t appear. I don’t understand exactly why. Lots of clinic and integrative doctors seems to recommend it. Where to classify it (I supposed it was oxidant, but it becomes unclear).

    Can we add it to an oxidative strategy ? Does anyone know ? Not necessarily Daniel : he will be exhausted with all these questions !

  16. Hello,

    And what about PH ?

    Because of one of your article, it seems that an oxidative strategy would be more efficient if we lower stomach acid. Stomach, so you talk about medicines : omeprazole and other – oles.

    Do you think that drink water with PH above 7, or take baking soda is a good idea ? (in particular if we drink coffee)

    Thank you very much for informations about this very important point.

  17. Hi,
    I would really like to know how hyperbaric chamber fit in with creating ROS.
    because in the above comments it says that it increased the Glutathione in the body which I guess is not a good thing.

    I am about to start Chemo tablets 2 weeks on and 1 week of. I also do IV vit C 3-4 weeks long, 2-3 times a week. And I have a hyperbaric chamber at home.
    And I am also taking a lot of drugs and supplements mentioned in the above article.
    I would like to create a structure as I don’t really know how to achieve the best result.

    Thank you so much
    Looking forward to your reply

    Jolanda

    1. Dear Jolanda,

      Thank you for your question. Normally, I would think that the hyperbaric chamber should be fine. However, there seem to be multiple reports indicating increased glutathione following HBOT https://sci-hub.st/https://link.springer.com/article/10.1007%2Fs12035-014-8705-x So it is difficult to say if it makes sense to use it or not here as I see both pro and contra arguments in this case, from a scientific point of view.

      Regarding the drugs and supplements, if you find it helpful, you can send me the excel by e-mail showing on a timeline how you intend to implement in respect to chemo and I will give you my feedback.

      Kind regards,
      Daniel
      Daniel

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