Friday 13 April 2018

The combination of DCA and a high dose of R-lipoic acid.


The MetaBloc protocol, which includes 800 mg of R-lipoic acid BID, looks interesting.
At the same time, the administration of DCA looks promising. It is reported that R-lipoic acid (form of alpha-lipoic acid) reduces the side effects of DCA.
Now my mom takes together DCA (8mg / kg / BID) and R-lipoic acid (800mg / BID).

However, I found an unexpected opinion about this!!! ↓↓↓

https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy/#comment-4502

“The difference between DCA and ALA is that DCA increases the production of ROS already overexpressed in cancer cells, such as chemotherapy to trigger either apoptosis, autophagy or necrosis of cancer cells. ALA on the contrary will tend to reduce the production of ROS to its normal threshold as in a healthy cell, thus triggering apoptosis if the cell detects a corruption of its DNA. In fact the overproduction of ROS, at the first level will lead to DNA corruption (cancerous state), to the next level we have apoptosis, then autophagy and then necrosis. Thus, with chemotherapy, such as DCA, cancer cells are destroyed by increasing their ROS production, but at the same time healthy cells are transformed into cancer cells by increasing their ROS level in the first stage...

DCA and ALA fall into two opposing strategies, DCA acts by citotoxicity like chemotherapy or radiotherapy, ALA acts by bringing the cells back into their normal operating context (normal ROS level for example). ALA is often taken to correct the neurological effects of DCA, but as part of the cancer their actions cancel each other out, so avoid taking them together. When it starts with an anti-cancer treatment citotoxic, after a certain time it will have to be interrupted before it becomes too harmful for the healthy cells and give the relay to the immune system supported by supplements like ALA, HCA, curcumin, vitamin C, etc."

http://treatingglioblastoma.com/treatments/dichloroacetate_DCA.htm
"Incidentally, I have concerns about any chemo patient taking ALA because it is a powerful anti-oxidant and probably increases intracellular glutathione levels in cancer cells, thereby contributing to chemoresistance. In addition, Dr. Michelakis reports that DCA preferentially increases reactive oxygen species (ROS) in cancer, but not healthy cells, which helps induce apoptosis. I have concerns that ALA could also help reduce the effectiveness of DCA."

However, in this article it is written about similar mechanisms of action of DCA and alpha-lipoic acid:
http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf

"Inhibition of PDK with either α-LA, small interfering RNAs or dichloroacetate (DCA) shifts the metabolism of cancer cells from glycolysis to glucose oxidation. Such metabolic rewiring is effective in reducing cancer cell growth in mice. The efficacy of cytotoxic chemotherapy is enhanced by the combination of α-LA and HCA. Similarly, DCA enhances the efficacy of cytotoxic chemotherapy or radiation therapy."

http://www.portmoodyhealth.com/cancer-centre/integrative-cancer-therapies/intravenous-alpha-lipoic-acid-iv-ala/
"Furthermore, ALA is cofactor of pyruvate dehydrogenase, an enzyme that converts pyruvate to acetyl-CoA, which reduces the formation of lactate. Lactate is produced from glucose in excessive amounts by cancer cells, as a result of altered cell metabolism (a phenomenon known as the Warburg effect). ALA reduces the amount of lactate produced by cancer cells, slowing their growth rate (19,20). In this way, ALA is synergistic with DCA (dichloroacetate) in its ability to alter cancer cell metabolism."

In reports on the treatment of Medicor, DCA is used together with R-lipoic acid.
For example, here:
http://medicorcancer.com/metastatic-ovarian-cancer/
"The patient consented to DCA treatment and was started at 23 mg/kg/day (500mg p.o. b.i.d.), on a cyclic treatment of 1 week on, and 1 week off. She was supplemented with vitamin B1 100mg p.o. t.i.d., and R alpha lipoic acid 300mg p.o. t.i.d."

Stephen also writes in one of his comments:
"Notably, one of the mechanisms of alpha-lipoic acid (inhibition of PDK, pyruvate dehydrogenase kinase) is a mechanism shared with dichloroacetate (DCA)."

Your opinion? Is it possible to combine a high dose of R-lipoic acid and DCA?
Will not they counteract each other?

P.S. An interesting conclusion of this study:
http://www.anaturalhealingcenter.com/documents/Thorne/articles/R-Lipoic12-4.pdf
"In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA."
How can we use it? Take 800mg of NaRLA in three doses at intervals of 15 minutes?

Also, because of problems with the stomach, I consider intravenous administration of alpha-lipoic acid. What dose for one infusion should be taken to equal 800 mg of BID NaRLA? And how often to make such infusions? I find different options: daily infusions or 2-3 times a week.

9 comments:

  1. I've seen that comment on cancertreatmentsresearch before, and it occurred to me that the commenter didn't fully understand the mechanism of action of DCA. DCA is primarily an inhibitor of pyruvate dehydrogenase kinases (which negatively regulate the pyruvate dehydrogenase complex). By inhibiting PDK, DCA increases the activity of pyruvate dehydrogenase. Pyruvate dehydrogenase is the enzyme system that converts pyruvate to acetyl coenzyme A, which is then fed into the citric acid cycle in the mitochondria.

    DCA does lead to increased ROS production, but so does the normal functioning of mitochondria. I'm not sure that ROS are so critical to the mechanism of DCA that it could be reversed with antioxidants.

    The main comparison between DCA and alpha-lipoic acid is that DCA increases pyruvate dehydrogenase activity by inhibiting pyruvate dehydrogenase kinases, and alpha lipoic acid is a pyruvate dehydrogenase cofactor.

    I haven't seen any evidence to convince me that lipoic acid would counteract the effect of DCA. However there is a valid point in all this, that some antioxidants could aid cancer cell survival, especially when given during therapies that work mainly or to a large degree through reactive oxygen species generation (radiation for example).

    There is no experimental evidence that I'm aware of to show that DCA and lipoic acid should not be used together, but there is the very complex and sticky issue of the role of antioxidants in cancer therapy. A person could replace lipoic acid with DCA and avoid the antioxidant issue. Unfortunately there's more questions than answers with this issue and in the cocktail approach generally.

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    1. Stephen, thank you very much that you stay with us and help us every day! It is very difficult to understand a huge array of information and your thoughtful opinion is always very valuable to us!

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    2. An interesting conclusion in this study, which you sent:(https://www.ncbi.nlm.nih.gov/pubmed/25998848):
      "LA enhanced the cytotoxic effects of temozolomide, which makes it a candidate for a supplement in cancer therapy."

      I thought about intravenous injection of alpha-lipoic acid 600 mg / day. I wanted to do 2 droppers a week, and on the remaining days - oral R-lipoic acid (Na-RALA) 800 mg BID.

      Now I'm thinking about 5 daily alpha-lipoic acid droppers in 5 days of taking temozolomide. The question is, at what time to do droppers? Immediately after taking temozolomide, so that their concentration in the blood was maximum simultaneously? Any thoughts?

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    3. Most in vitro studies are hard to take seriously in my opinion, because they typically ignore all questions related to human pharmacokinetics. For example,

      "This is the first study to report negligible unbound RLA even at the highest achievable plasma concentrations."
      https://www.ncbi.nlm.nih.gov/pubmed/18069903

      With negligible unbound R-lipoic acid in plasma even at the highest plasma concentrations, it might quite a challenge to get the 40 - 50 micromolar concentration in the brain, which was shown to inhibit MGMT in vitro.

      It probably won't hurt though. I have a feeling that many of the supplements people use based on in vitro studies are harmless but probably ineffective. It's important to prioritize the higher level data (first clinical, and then in vivo) over the lower level (in vitro). For some cancers (blood cancers) it's easier to design experiments with realistic drug concentrations, because the human pharmacokinetic data and plasma concentrations of drugs can usually be found. Not so for brain tumors, where there's the massive pharmacokinetic issue of getting drugs into the brain at therapeutic levels.

      That said, if you want to have maximum plasma lipoic acid levels coincide with maximum TMZ levels, you'd have to consider the Tmax (time to maximum plasma concentrations) of lipoic acid, which looks to be around 50 minutes.
      https://www.omicsonline.org/scientific-reports/0975-0851-SR-418.pdf

      The Tmax for MTIC (the active conversion product of TMZ), is longer, 1.5 - 2 hours.
      http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000229/WC500035617.pdf



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    4. Interesting quote from this article:
      https://academic.oup.com/carcin/article/36/8/817/1851173

      "Commercially available dietary oral supplements typically contain between 50 and 600mg LA and result in plasma concentrations in low µM range, which are unlikely to affect MGMT levels. High LA plasma levels of up to 400 µM may only be reached during therapeutic intervention with high oral or intravenous administration (23,53). In this therapeutic setting, LA could predispose cells and tissues to alkylating agents as a consequence of MGMT inactivation. This warrants further studies in patients receiving high doses of LA over a longer period, such as patients with diabetic neuropathy."

      Incidentally, mice were injected with alpha-lipoic acid 6 days before TMZ and every second day after TMZ day.

      In this study, much attention is directed to the effect of alpha-lipoic acid on MGMT. It is not clear, will MGMT methylation have any meaning?

      It is also interesting, will alpha-lipoic acid increase the cytotoxic effect of another alkylating agent - Lomustine?

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  2. Interesting- so lipoic acid may not be the best option during chemotherapy? Would it make more sense to use DCA during chemo and then switch to lipoic acid afterward?

    And in terms of antioxidants and other supplements, which ones should we avoid during chemotherapy and which ones should we perhaps consider upping in dose? I am still searching through the Brain Tumor Library (which is an incredible resource!) so forgive me if it's already outlined there. Thank you!

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    1. The most comprehensive review of the subject of antioxidants and cancer therapy I know if the one authored by Ben Williams.

      http://virtualtrials.com/pdf/williamssupplements2014.pdf

      Some antioxidants seem to have protective effects for healthy tissue while not interfering with the efficacy of standard treatments. On the other hand some antioxidants have been shown to interfere with standard treatments in experimental rodent models. For example:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266032/
      Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

      and one study found an negative association between vitamin E and survival for brain tumors, that was borderline significant (p=0.09), perhaps because of interference with the effects of radiotherapy.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671323/

      Each antioxidant has to be considered individually and each standard treatment or chemotherapy probably has a different potential to be reversed by antioxidants. Some chemotherapies probably don't rely on ROS in their mechanism of action at all. It's an enormously complicated topic. I can't say I have an answer to your question.

      If you Google "lipoic acid" and "temozolomide" you can find studies such as this one, showing that lipoic acid can actually inhibit MGMT in vitro and sensitize cells to TMZ.

      https://www.ncbi.nlm.nih.gov/pubmed/25998848

      Whether this is is relevant in vivo, or in humans, depends on if they were using physiologically achievable concentrations of lipoic acid, which might not be the case.

      I've not seen any studies showing that lipoic acid would interfere with chemo. This study might also be relevant:

      https://www.ncbi.nlm.nih.gov/pubmed/24362907

      Lipoic acid has been used to prevent radiation injury to healthy tissue in animal models:

      http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=20286&path[]=64682

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    2. That's all very interesting and helpful, thank you Stephen! I know there's no simple/direct answer but I appreciate all the info.

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  3. "Do Anti-Oxidants Vitamin D3, Melatonin, and Alpha-Lipoic Acid Have Synergistic Effects with Temozolomide on Cultured Glioblastoma Cells?"

    https://www.ncbi.nlm.nih.gov/pubmed/29925764
    http://www.mdpi.com/2305-6320/5/2/58/pdf

    Conclusions: Anti-oxidants may have synergistic effects with TMZ. LA offers the most promise, followed by melatonin.

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