Antioxidants - Pro-oxidants.

[pjoshea13]

It's common to reconsider diet following a cancer diagnosis. Perhaps give up foods touted as pro-cancer & load up on those thought to be protective. As though what we should have been eating before, is what we should be eating henceforth.

But what if the cancer likes the new diet?

It's widely accepted that free radicals in the body, being inherently unstable, may cause DNA damage (& therefore cancer) & that antioxidants from a diet rich in non-starchy vegetables may provide sufficient antioxidants to counter those free radicals.

I have known two men who hoped to coax their PCa cells back to normalcy via a "healthy" diet. The idea being that the cells would somehow become better differentiated & less dangerous. Meanwhile, BigPharma takes the opposite approach. Cancer treatments generally involve the generation of reactive oxygen species [ROS]. Antioxidants in the diet might water down the therapeutic ROS effect.

We bring into PCa, dietary baggage that cannot automatically be assumed to be useful. Unfortunately, dietary advice from the gurus is often just more of the same. Did Dean Ornish make any changes to his standard 10% fat vegan diet for his PCa clinical trial? The diet is supposed to be perfect for all circumstances. Perhaps he had doubts, though, since he slipped in a little fish oil, but otherwise changed nothing. Vegans quite rightly were angry with him.

PCa has an extraordinary wide phytochemical literature (mostly polyphenols). These chemicals have protective roles in plant life. There are two common features: (i) they inhibit NF-kB (nuclear factor-kappaB), the chronically-activated cell survival protein complex, & (ii) they are antioxidants.

But why might an antioxidant be found useful against cancer? Invariably, the phytochemicals only became effective in studies at levels where ROS was induced. At high levels, an antioxidant may become a pro-oxidant.

I often see some variation of the following statement:

"Pretreatment with N-acetylcysteine (NAC) inhibited both ******-induced ROS generation and growth inhibition."

NAC itself can become pro-oxidant at very high levels, but it is generally a reliable ROS scavenger. Thus, if we take a pharmacological dose of polyphenols, in order to encourage ROS, we should stay away from NAC. (I'm also wary of alpha lipoic acid [ALA]. ALA is a very fine supplement for those without cancer, but might undermine ROS-related therapy.)

I dredged up a number of PCa-phytochemical studies, below, to make the point that we need pro-oxidant doses. It isn't an exhaustive sample, however.

[A] Apigenin, a flavone.

[A0] Source: "parsley, celery, celeriac, and chamomile". Supplement from grapefruit.

[A1] "Apigenin generated reactive oxygen species, a loss of mitochondrial Bcl-2 expression ..."

[A2] "Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis."

[Ca] Capsaicin

[Ca0] Source: chili peppers.

[Ca1] "The results showed that capsaicin induced prostate cancer cell death in a time- and concentration-dependent manner" in LNCaP and PC-3 cells.

"Furthermore, we found that capsaicin triggered ROS generation in cells, while the levels of ROS decreased with N-acetyl-cysteine (NAC) ... Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death."

[Ch] Chrysin. A flavone.

[Ch0] Source: propolis. Supplement: passionflower. Bioperine for bioavailability.

[Ch1] "chrysin induced apoptosis of cells evidenced by DNA fragmentation and increasing the population of both DU145 and PC-3 cells in the sub-G1 phase of the cell cycle. In addition, chrysin reduced expression of proliferating cell nuclear antigen in the prostate cancer cell lines compared to untreated prostate cancer cells. Moreover, chrysin induced loss of mitochondria membrane potential (MMP), while increasing production of reactive oxygen species (ROS) and lipid peroxidation in a dose-dependent manner."

[Cu] Curcumin.

[Cu1] "curcumin induced ER {endoplasmic reticulum} stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress.

[Cu2] A curcumin analog (WZ35).

"we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35."

[Ga] Gallic acid.

[Ga0] Source: Indian gooseberry. There is some in tea leaves.

[Ga1] "Gallic acid (GA) is a natural polyphenol, and we tested its in-vitro cytotoxicity after 24 h in prostate cancer LNCaP cells." "Increased intracellular ROS levels with GA were reduced by N-acetyl-L-cysteine (NAC) and L-glutathione (GSH). Cells were protected against GA cytotoxicity when pretreated with increasing levels of superoxide dismutase/catalase mixture, NAC, or GSH for 3 h"

[Ge] Genistein. An isoflavone & phytoestrogen.

[Ge0] Source: soy. LEF product.

[Ge1] Genistein was added to Doxorubicin Hydrochloride to amplify oxidative damage.

[P] Phenethyl isothiocyanate (PEITC)

[P0] Source: some cruciferous vegetables, but particularly watercress.

[P1] "PEITC significantly inhibited DU145 cell proliferation in a dose-dependent manner and induced the cell arrest at G2-M phase." "Moreover, an antioxidant reagent, N-acetyl-L-cysteine (NAC) which suppresses reactive oxygen species (ROS) generation, reversed the early inhibitory effects of PEITC on cell proliferation"

[S] Sulforaphane.

[S0] Source: Source: some cruciferous vegetables. BroccoMax.

[S1] "Sulforaphane-induced apoptosis in PC-3 cells correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential" "The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation"

[NAC]

"Discordant results in preclinical and clinical trials have raised questions over the effectiveness of antioxidants in prostate cancer chemoprevention. Results from the large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that antioxidants failed to prevent, and in some cases promoted, prostate cancer formation in men without a history of the disease."

"{We treated} Nkx3.1 mutant mice with the antioxidant N-acetylcysteine (NAC) for 13 weeks post-weaning. Surprisingly, while NAC treatment decreased ROS levels in Nkx3.1 mutant mouse prostates, it failed to reduce prostatic epithelial hyperplasia/dysplasia. Rather, NAC treatment increased epithelial cell proliferation and promoted the expression of a pro-proliferative gene signature."

[X] Drugs.

[XC] Cabazitaxel [Jevtana]

[XC1] "Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production"

"To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel."

-Patrick

[A0] swansonvitamins.com/swanson...

[A1] ncbi.nlm.nih.gov/pubmed/154...

[A2] ncbi.nlm.nih.gov/pubmed/183...

[Ca0] swansonvitamins.com/natures...

[Ca1] ncbi.nlm.nih.gov/pubmed/266...

[Ch0] swansonvitamins.com/swanson...

[Ch1] ncbi.nlm.nih.gov/pubmed/?te...

[Cu1] ncbi.nlm.nih.gov/pubmed/260...

[Cu2] ncbi.nlm.nih.gov/pubmed/265...

[Ga0] swansonvitamins.com/swanson...

[Ga1] ncbi.nlm.nih.gov/pubmed/225...

[Ge0] lifeextension.com/Vitamins-...

[Ge1] ncbi.nlm.nih.gov/pubmed/294...

[NAC] ncbi.nlm.nih.gov/pubmed/230...

[P] en.wikipedia.org/wiki/Phene...

[P1] ncbi.nlm.nih.gov/pubmed/194...

[S] Sulforaphane.

[S0] swansonvitamins.com/jarrow-...

[S1] ncbi.nlm.nih.gov/pubmed/189...

[XC] en.wikipedia.org/wiki/Cabaz...

[XC1] ncbi.nlm.nih.gov/pubmed/291...

[snoraste]

I just posted a question on sulforaphane related (somewhat) to your post here. But I have to admit I have a conceptual problem with this low dose/high dose. It is a little hard to accept that the impact (pro/anti oxidation) flips at an arbitrary threshold level of dosage. It can't be that abrupt. But I do realize that's what the research maybe suggesting. What it is also suggesting - which is more of a scandalous claim - is that what you thought were good for you (all the exact same chemicals in the fruits/veg) could be now bad for you if taken in low dosage as food. Do you actually believe in it? or is there something amiss?

[pjoshea13 in reply to snoraste]

Well, I certainly don't avoid vegetables that have a good nutrient profile. For a lot of delicious fruit, however, the sugar to nutrient ratio is a problem for me. Strawberries & blueberries are good, though.

Some radiologists say to avoid antioxidants during treatment. Others say it probably doesn't matter. But it's pointless for a patient to try to counter oxidative stress, while udergoing treatment that is trying to induce it.

-Patrick

[Hidden in reply to pjoshea13]

Those videos were great! I loved the watermelon being so good for us. My favorite . My radiologist said no anti-oxidents or high dose vitamins during Rt. I did high dose C,B,dmso I V ‘s and nutrients during RT anyway. A year later all clear.Same doc said whatever you’re doing keep doing it. I dont have funds to to do what I did the first year.I feel that it helped me a lot in the beginning fighting to survive. We are all trying to out wit or out last or live with APC ... Good luck to all in finding their path with APC.

[Hazard]

Thanks again Patrick for some very informative research. This post really struck a chord with me - as I reported elsewhere on this forum, I adopted a full 'guru' plan in early 2017 - raw, planted-based diet and lots of supplememts. This made no difference at all to PSADT of 30 days. I hasten to add that I stuck to my convential medical plan in parallel with this and I started ADT May 2017. After a brief 3 month reprieval, castrate resistance emerged and PSADT resumes its regular 30 day rate.

Chemo (docetaxal) started Dec 2017 and after 3 rounds, PSA has dropped from 47 to 3.6. So my personal experience clearly supports the clinical evidence that you have presented - diet /antioxidants don't do anything to slow cancer, ROS via chemo does.

Which brings me to my main question. When my PCa was first diagnosed I did a lot of google searching like many of us do. I came across a thing called 5 minute cancer cure which involves ingestion of Hydrogen peroxide 1 drop in a glass of water on day 1, dose increaeses 1 drop a day until it reaches 25 drops. Now I dismissed this out of hand at the time but now I am starting to think that maybe this is not such a bad idea. Hydrogen peroxide is a strong pro oxidant so maybe it really will help. Have you read any literature about this? I could ask my MO but he doesn't want to hear any more stories from me that start "Patrick and/or Nalakrats said ... what do you think?" 😆

I really enjoy your posts, thanks for all the great information.

[pjoshea13 in reply to Hazard]

Hi Hazard,

I'm a H2O2 sceptic.

Hydrogen peroxide will damage cells that it comes into contact with, & it has to be in contact with a lot of cells before reaching PCa cells.

Oral H2O2 will break down in the stomach & produce gas.

IV H2O2 will destroy platelets.

While the body does produce H2O2 in certain circumstances, cells will quickly generate catalase to remove H2O2 (2H2O2 will become 2H2O & O2). A smart bomb that safely delivers H2O2 to cancer cells? Could that work? Maybe.

-Patrick

[Spaceman210]

What about the equivalent human dosage at which such agents / anti-oxidants have shown to be pro-oxidant and cancer fighting during therapy? I haven't seen this anywhere yet except for references to intravenous high-dose Vitamin C.

[jazj]

I know this is an old post but I'm doing some antioxidant research. I think it's important to point out, this post is in the context of a forum where particpants mostly are currently confirmed to have Advanced Prostate Cancer. I had Gleason 7, but PSA of 29 (partly due to more rare interior location of the tumor experienced by only about 20% of PCa patients which typically has higher PSA), but the PSA alone technically put me in the "High Risk" category. My post-prostatectomy pathology looked good. No positive surgical margins or capular extension. My 6-month Ultra Sensitive PSA test was undetectable (< 0.02). However I still don't consider myself out of the woods as there could be PCa stem cells still lurking.

My general philosophy is to eat a good diet (Flexitarian/Medditeranean) and lots of vigourous exercise maintain BMI < 25 are the main things that probably make the most difference with least risk of being counterproductive. The thing I won't give up is my red wine 2 glasses most nights, on ocassion 3. Studies have shown 1 glass isn't an issue as the ellagic acid and polyphenols can actually be a positive, but more than one and you are looking at producing some oxidative stress.

So what about people trying to minimize the chance of biochemical failure and recurrence of PCa?

In those "healthy" individuals, it seems to mean producing ROS wouldn't we wise. Not just for PCa but related to risk of develping other cancers. It seems to me moderate doses of antioxidant supplements for those in remission may be the better choice rather than dosages that produce ROS. Also for many substances as the amount used in in-vitro and in-vivo studies usually translates to an insanely (typically unrealistic) high dose of the substance taken as a supplement in real-life.

So I think for those diagnosed with PCa in the low-risk category with non-rising PSA and for those in remission, with undetectable PSA, I don't think taking huge antioxidant doses to cause ROS is a wise choice in my own opinion. (I don't think Patrick was suggesting that either?)

For those with growing, detectable PCa, it is widely advised to avoid antioxidants when receiving radiation or chemotherapy. In fact, some studies regarding Women taking antioxidants before and duriing treatment had stastically significant worse outcomes as far as reccurrence and mortality.

aicr.org/news/vitamin-suppl...

oncotarget.com/article/2820...

However I agree with Patrick, that taking antioxidants to induce ROS may be the better way to go when you have confirmed, growing PCa. This is why you have studies looking at the effects of extremely high intravenous doses of Vitamin C (which wasn't a silver bullet.) Essentially you are giving yourself your own chemotherapy treatment. But how high a dose of which supplements is required?

I realize this forum is primarily for Advanced PCa patients but I think the disucssion of how to prevent reaching an advanced stage in the first place are relevant to the subject in general.