I have read several papers indicating a connection between the process referred to as "methylation." It's complicated, as is everything connected with prostate cancer and, to be truthful, I find it very difficult to follow the discussions in these papers. Therefore, I am putting this communication out there for commentary from those of you who understand methylation. It appears, that cancer sells may grow when it is too prevalent by utilizing, for their benefit, the glutathione created during Methylation. Glutathione normally protects cells from ROS. Why am I concerned? If this is true, cancer patients need to pay attention to whatever contributes to methylation or increases their glutathione levels. For example, I have stopped taking folate and N-Acetyl-L-Cysteine. I was sorry to give up the NAC because it, among other things, is a good detoxifier of the liver and, considering all of the toxins (read: medications) that I am exposed to on a daily basis, this is a big drawback. Can anyone clarify for me how to deal with methylation (we need it, but not too much!), so that I may, through diet, benefit from it, yet not suffer any adverse effects. Thanks.
Methylation or not?: I have read... - Advanced Prostate...
Methylation or not?
Hi Kuanyin,
This is a topic that I am close to - having had my PSA doubling time shorten considerably after injecting vitamin B12.
SAM is the universal methyl donor in the body. If we were free of cancer, we would let it do its job. Unfortunately, PCa has an appetite for methyl. It wants to be hypermethylated.
In normal cells, the DNA regions responsible for tumor suppressor genes are never methylated. In PCa cells, they are invariably methylated - silenced.
This is an epigenetic change & can, theoretically, be reversed.
You write "I have stopped taking folate". Presumably, you live in a country where folic acid is not added to grains?
Folate is the main methyl donor from the diet, & intake can be restricted. Very difficult in countries where it has been added to bread & rice.
Other B viamins are needed to make the methyl available to SAM (the methyl mailman). B12 is one of them. Older men can sometimes have a B12 uptake problem. This can be a good thing in PCa, since with inadequate B12, the methyl in folate can't be released.
You mention stopping N-Acetyl-L-Cysteine. If you take high doses of polyphenols for PCa, such as curcumin or resveratrol, these antioxidants become pro-oxidant & generate ROS. NAC is almost always operating as an antioxidant & will negate any benefit from the polyphenols.
Conventional cancer treatments often depend on ROS & NAC will mess with them too.
-Patrick
Hi Patrick,
Thank you for your prompt reply and brief explanation of the methylation process. I read a paper (Epigenetics: A New Bridge between Nutrition
and Health) in which there is a discussion of supplements that may help in demethylation or counter the effects of methylation. The paper mentions a possible cancer therapy, "
Synergistic Cytotoxicity of Artemisinin and
Sodium Butyrate on Human Cancer Cells" (actually the title of another paper) to counteract the results of methylation. Just wondering whether or not you are familiar with this "therapy" and have any thoughts on the matter.
Does Vitamin E become pro-oxidant and generate ROS.
Rich
Rich,
Vitamin E is one of those supplements where I have never been tempted to take a high dose.
You might be interested in:
ncbi.nlm.nih.gov/pubmed/170...
& smokers need to be wary:
ncbi.nlm.nih.gov/pubmed/113...
-Patrick
Patrick, can you say generally, how much curcumin would switch to pro-oxidant? Can you also remind me what 'generate ROS' means.
After years of being in this, there comes a time when saturation gets the best of one.. I may be there.
You are calling curcumin and resveratrol a polyphenol. Right? Then this sentence:
" NAC is almost always operating as an antioxidant & will negate any benefit from the polyphenols."
I've read this over and over. My understanding is it's the pro-oxidants either by conversion or not, that can interfere with apoptosis or killing PCa. So," NAC is almost always operating as an antioxidant" (which would be good) right?
you go on to finish that sentence with .." & will negate any benefit from the polyphenols."
I get the high doses that convert, but I don't get NAC and that sentence.
Can you clarify this?
Thanks genie..
Hi Genie,
I am going to be a bit evasive here. Typically, a physiological dose, as from food, will be an antioxidant. A pharmaceutical dose, far higher than from food, would be pro-oxidant.
Since we need to induce oxidation (reactive oxygen species - ROS) as the first step to killing the cells, err on the side of a very large dose.
NAC will prevent curcumin & resveratrol from being pro-oxidant, so is to be avoided.
My feeling about curcumin & resveratrol is that one must look for proven bioavailability, so as to avoid taking handfuls of capsules.
revgenetics.com/store/p-32-...
swansonvitamins.com/now-foo...
Best, -Patrick
In Volume 138, Issue 1, April 2013, Pages 1–17
of the journal "Pharmacology & Therapeutics" the following paper appears "Epigenetic modifications by dietary phytochemicals: Implications for personalized nutrition." To save everyone the trouble finding the article, I will quote the entire abstract below:
Abstract
In the last two decades, the study of epigenetic modification emerged as one of the major areas of cancer treatment targeted by dietary phytochemicals. Recent studies with various types of cancers revealed that the epigenetic modifications are associated with the food source corresponds to dietary phytochemicals. The dietary phytochemicals have been used in Asian countries for thousands of years to cure several diseases including cancer. They have been reported to modulate the several biological processes including histone modification, DNA methylation and non-coding microRNA expression. These events play a vital role in carcinogenesis. Various studies suggest that a number of dietary compounds present in vegetables, spices and other herbal products have epigenetic targets in cancer cells. Dietary phytochemicals have been reported to repair DNA damage by enhancing histone acetylation that helps to restrain cell death, and also alter DNA methylation. These phytochemicals are able to modulate epigenetic modifications and their targets to cure several cancers. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, the personalized nutrition will help us to prevent various types of cancer. In this review, we will discuss the effect of dietary phytochemicals on genetic and epigenetic modifications and how these modifications help to prevent various types of cancers and improve health outcomes.
Some of the foods mentioned are tomatoes, tumeric, cinnamon, cashew nuts, apples, soybean, green tea, grapes, citrus, broccoli, coffee and garlic--no surprises here. I don't know how much of this stuff one would have to eat each day and there's probably no sane way to find out. However, what one could do is purchase one of freeze dried or powdered supplements that contain many of these foods in concentration. This is what I am currently doing. One has to be careful because many of these supplements contain as their main ingredients "grasses." I try, whenever possible, to stick with vegetables and fruits. I usually stir in a measure of this with my vitamins and supplements (Again, whenever possible, I take the time to open each capsule into my blender and add a packet of Emergen-C to make the drink fairly palatable. You might want to add a teaspoon of olive oil for the oil soluble vitamins and tumeric.)
A "methyl group" is a carbon atom covalently bonded to three hydrogen atoms. It has one valence electron left that is not bound to anything and can easily bind to other molecules. I think that methylation, as it relates to cancer, consists in the replacement of a hydrogen atom on a DNA base molecule with a methyl group. When DNA is methylated (or acetylated, a similar process but with an acetyl group instead of a methyl group), the physical shape and electrical characteristics of the DNA base molecule are altered and it can no longer perform its usual function.
DNA methylation is a normal and healthy part of ordinary life. It is used by cells to prevent the expression of certain genes. If the wrong genes get methylated, for example genes that suppress tumors, the chances of developing cancer can increase. However if genes that should be methylated are not, for example "oncogenes" that promote cancers then, again, the chances of developing cancer can increase. But the problem is a deep one in that the expression of genes that suppress or promote cancer is generally regulated by the expression of other genes, so methylation of those genes is also a factor in cancer.
I'm at best an amateur in molecular biology, but I have some doubts that anyone can enable good methylation to occur, or bad methylation not to occur, by modifying their diet. I suspect that the levels and targets of methylation have much more to do with mutations in DNA that promote or suppress the methylation of other genes than with the availability or lack thereof of methyl groups. I'm not even sure that it's possible to restrict the availability of methyl groups by diet since they are in many kinds of food and I wouldn't be surprised if they can be synthesized in the body.
I sometimes think that rocket science is a piece of cake compared to molecular biology and biochemistry. The subject is so immensely technical that it's at least very difficult, and more likely impossible, to figure out any useful medical interventions based on biochemical theory without having an enormous background in both theoretical and laboratory work. Even then, the most educated guesses often turn out to be wrong when tried in the laboratory. That's one reason why progress in cancer treatment is so slow, even though some real geniuses are working on the problems.
Alan,
Nevertheless, a demethylation drug has been approved by the FDA for Myelodysplastic syndrome:
" Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status.[2][3] Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells."
en.wikipedia.org/wiki/Demet...
You write:
"When DNA is methylated (or acetylated, a similar process but with an acetyl group instead of a methyl group), the physical shape and electrical characteristics of the DNA base molecule are altered and it can no longer perform its usual function."
Acetylation is required in order to access the DNA, which is tightly wound around histones. The counterpart to methylation silencing involves HDAC (histone deacetylase), which reverses acetylation.
Thus, effective elimination of PCa epigenetic changes might require a demethylation agent & a HDAC inhibitor. An HDACI that has been around a long time is valproic acid:
en.wikipedia.org/wiki/Valpr...
"The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects."
It was used in a Phase I PCa trial:
ncbi.nlm.nih.gov/pubmed/280...
There have been in vivo studies too, not just cell studies - e.g.
ncbi.nlm.nih.gov/pubmed/230...
-Patrick
Patrick,
Reading your post and reading the documents, I see that this research is further advanced than I realized, though it's clearly still at an early stage. In the stage one clinical trial that included valproic acid, I see that that drug was combined with bevacisumab. 15% of patients in the trial achieved the trial's goal of confirmed stable disease of greater than 4 months, and it appears that half of those made it to greater than 6 months. But I can't tell from reading the abstract how much of that achievement was produced by the valproic acid, how much by the bevacisumab, and how much might have been due to other factors. And of course 85% did not achieve the 4 months of stable disease goal.
When a patient has run out of other options, it can make sense to try something exotic. But before then, I'm not sure I'd recommend it to anyone, most especially if it is being tried without the support of an experienced doctor/oncologist who has done research in that area.
On the lighter side, I noticed when doing a little Googling that there is a Dr. Mark Hyman, "Medical Director at Cleveland Clinic’s Center for Functional Medicine, the Founder of The UltraWellness Center, and a ten-time #1 New York Times Bestselling author." He has a web page on methylation. See drhyman.com/blog/2011/02/08.... I'm not convinced that he knows anything about methylation but it looks like he's pretty good at performing surgical extractions on the wallets of well to do patients.
Alan
Hi Alan,
Thank you for your reply. Your answer indicates why I have had such difficulty getting a handle on the issue of methylation. My oncologist's office hands out a sheet of suggested do's (exercise regularly) and don'ts. Among the "don'ts" are no exogenous folate and vitamins to avoid. Obviously, the load of these substances dumped into our foods cannot be considered: it's not like buying gluten-free bread. It would be too hard to avoid. Anyway, on my last visit to the oncologist's office, at the end of my visit, the oncologist asked me whether or not I had a question concerning my prostate. With certain doctors, I have taken to keeping my mouth shut: they really don't want any questions! However, I did mention methylation and how complicated it seemed to be. Without taking his eyes from his laptop screen, he mumbled "yes" and that was the end of the "discussion." Problem is, Alan, most of the people who participate in this forum really want to play an active part in their own treatment. Unfortunately, the nature of this disease, because of the hormonal interconnections, with their endless pathways, genes, enzymes, etc., prevents the layperson from obtaining even a modicum of understanding of what's going on with his illness. You are probably correct in assuming we are probably cobbling together the elements of methylation in our own bodies from diverse sources. However, I no longer take additional folate and limit my B12 to a sublingual lozenge twice a week to keep my homocysteine values down. Unfortunately, this is tied to methyl donors (B12, folate, TMG, B5B).
Hi Kuanyin,
I understand the desire to do something. We don't like to be passive in the face of our disease. When I was being treated some years ago (I seem to be okay now - cured or in long term remission due to my radiation + ADT treatment) I took lots of lycopene, green tea extract, pomegranate extract, and other things that were recommended at the time. I don't know if any of them are still recommended, but it helped me to feel that I was doing something, not just waiting to see whether the docs could kill the disease before it killed me.
But I've come to believe that our understanding of these things is so far from complete, and the published research so skimpy and even biased by companies that manufacture supplements, that I'm not optimistic about figuring out what actually helps.
Here's an interesting article about methylation:
ncbi.nlm.nih.gov/pmc/articl...
It's already old (2010), but it looks well written to me. You can see how highly technical it is and how difficult for a layman to understand, or even for a scientist to use in making clear treatment recommendations. It looks to me like it's talking about processes that can influence both the growth and the retardation of cancer, but it seems very far from enabling someone to be able to say with any confidence: "Eat two grams of this per day. Don't eat that other thing. The effect will be an average 47% reduction in the rate of growth of your cancer."
I'm optimistic about the work that the scientists are doing. I'm not so optimistic that this kind of very basic research translates directly into prescriptions for treatment. I think it will require years of additional lab work and years of trials before we know how to use the new information.
Alan
My sense is that methylation is a very basic and common mechanism in cells with a nucleus to control the sections of DNA that are exposed for gene expression; a way to make cells that have the same DNA seem (and be) so different
The sections of DNA that are available for gene expression are called "euchromatin", as opposed to "heterochromatin" . I had thought that euchromatin was methylated, but now I think the methlyated CpG's mark the start of inactive sections.
Whether this has to do with the DNA winding around the histones, or with an interference with DNA binding regions of transcription factors, no idea.
Hi Kuanyin,
I have been struggling with high homocysteine and if I should do anything about it. I have been reading all the posts about methylation and searching articles on the web. I found an article that says that the following supplements, which many of us take, can raise homocystine levels:
Quercetin, Melatonin, Astragalus, Curcmin
Link: selfhacked.com/blog/optimal...
Link: ncbi.nlm.nih.gov/pubmed/247...
I was taking many grams of curcumin. I might stop and shift to different supplements to see if the homocysteine drops.
-Dave
Thanks Dave. I already knew that my Metformin influenced H levels, but not to what degree. Adding insult to injury, I take 1500 mg of Quercitin a day! The curcumin article, as I read it, is not critical of curcumin. Take a look at this:
"Epigenetic changes induced by curcumin and other natural compounds." ncbi.nlm.nih.gov/pmc/articl... .
"This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment." So, I don't think there is a problem with the curcumin. It's the Metformin and Quercitin, at least in my case.
I am scheduled for my next blood work in two weeks. We'll see what my homocysteine number is at that time. I can reduce the Quercitin. However, if need be, I'll also have to stop the Metformin as well. Thanks, again for the articles.
K.
To state the obvious: early use of Zytiga or Xtandi extends survival in APC
Chemo or no/not yet?
DNA Methylation Readers and Cancer: Mechanistic and Therapeutic Applications
