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Advanced Prostate Cancer
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Some Difficulties Translating Scientific Studies into News We Can Use

I recently re-read a paper that was discussed in this forum over a year ago. I bring it up now because I have re-thought some of the supplements I presently take and plan to make changes in my regimen. The paper in question, “Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism, NPJ Precision Oncolog (2017) 1:18 ; doi:10.1038/s41698-017-0024-zy.”

On one level, the results of this study are very useful because it provides the names of the most effective plant-based supplements available.

“High-throughput screening of [142] natural compound library was performed to identify the most efficacious combinatorial treatment on prostate cancer. Ursolic acid, curcumin and resveratrol were selected for further analyses and administered in vivo via the diet, either alone or in combination, in a mouse allograft model of prostate cancer. All possible combinations of these natural compounds produced synergistic effects on tumor size and weight, as predicted in the screens. A subsequent untargeted metabolomics and metabolic flux analysis using isotopically labeled glutamine indicated that the compound combinations modulated glutamine metabolism. In addition, ASCT2 levels and STAT3, mTORC1 and AMPK activity were modulated to a greater extent by the combinations compared to the individual compounds. Overall, this approach can be useful for identifying synergistic combinations of natural compounds for chemopreventive and therapeutic interventions.”

The entire study is available with all of the details. The study reveals its failure on another level, namely the results are given in “uM”

HMVP2 cells were screened at three different concentrations (5, 10 and 20µM) and three time points (12, 24 and 48h). Z-factors were calculated to evaluate cell response (based on ATP suppression) following exposure to the natural compounds.

A Z-factor value greater than 0.5 was considered a very good response. The 20µM treatment resulted in the highest number of compounds with Z-factors greater than 0.5 and ATP values lower than 0.5 (indicating good suppression) and was therefore selected as the best dose for the selection of the top hits (Fig. 1, ATP only). ATP and the derived Z-factors for all treatments and all doses are included in Supplementary Table 1. ATP suppression in treated HMVP2 cells varied greatly, with the majority of the screened natural compounds inducing a moderate drop in ATP concentration to >50% of control (Fig. 1). Notably, after 12h of treatment at the 20µM dose, the majority of the natural compounds under study induced a greater suppression of ATP levels compared to untreated (solvent control) samples than longer treatments at the same dose.

The so-called “top hits” were Ursolic Acid, Curcumin, and Reservatrol. However, 20uM

refers to the screening of HMVP2 cells, how well or poorly they did with the combinations. It doesn't tell us the concentrations of these natural compounds fed to the mice. If someone out there can translate uM into mg/kg please do so. It is not easily converted because these are two different ways of measurement.

So, I called up the lab at which the study was done and asked to speak to the person who wrote the paper. I learned that she had moved on and was no longer employed there. The person with whom I spoke said she had taken that individual's place. I therefore asked her to answer the question. In turns out that she was unable to make such a conversion and that she had received other calls from “laypeople” asking similar questions. The answer she was told to give us is “take a copy of the paper to your physician to discuss with him.” At this point I became a little difficult: I told her that although I realize the paper was written for peers, nevertheless, it was irresponsible to publish such results. How does the reader not know that these mice were given hundreds of grams to obtain these results? If true, then there is no way in the world that someone could even attempt to mimic the therapeutic amounts fed to the mice. She finally agreed to speak with the researchers and get back to me.

Meanwhile, we learn that there is an on-going trial of curcumin at 500x2 (See cesanon) . If this is an effective dose, the paper in question reveals that a combination of the three winners is more effective than single doses of one supplement. It would be a good starting point.

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Be careful of trying to extrapolate to humans from Mouse studies - everything works in mice.

On curcumin, read:

pubs.acs.org/doi/10.1021/ac...

Since you like mouse studies, here's one on resveratrol that you should read:

ncbi.nlm.nih.gov/pmc/articl...

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It might be a simplistic view but when I look at worldwide prostate cancer incidence statistics I see that India is one of the countries with the lowest incidence, so they must be doing something right.Could it be related to their diet which includes high amounts of Curcumin since infancy? I tend to believe so.

On the other hand, France is quite high in the table. So ,following my simplistic analysis, it raises questions regarding the benefits of Resveratrol

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India has low rate of cancer due to high levels of curcu.en (via tumeric) in their diet? Well that is a very simplistic analysis of data. Average life expectancy of men in India is 63, in USA life expectancy of men is 82. So their is a case to say that high levels of tumeric in the Indian diet leads to low life expectancy. But only if you select single bits of data that support your argument. Yes you view is very simplistic and does not withstand any critical analysis for more than 1 second.

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Interesting...

My point was to say that there "might" be a relation between Indian diet and prostate cancer incidence.Is like saying that a Mediterranean diet is better for you health (based on real world statistics)

While indeed the incidence is very low, mortality from it in India is one of the highest which seems to correlate with your input about life expectancy and does not have any relation whatsoever to cancer incidence.

Saying that a diet with a high amount of Curcumin might be related to prostate cancer incidence seems more based than following some aussie health guru and thinking that going veggetarian might improve your chances

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Ha ha got me there 😀.

In my defence all I can say is that when surgery and radiation fail and your doctor wants to castrate you, sometimes you will try anything. Clearly the plant based det hasnt made a bit of difference to PCa but at least it has helped my general health.

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I agree with Hazard - it is way too simplistic to attribute Indians not getting as much cancer to curcumin. In addition to all the other aspects of their diet, there's genetics, soil, microbiome, sunshine, etc. I think Hazard gave up too quickly on the age thing - cancer is mostly a disease of older people. If the Indian people don't survive long enough to be detected with prostate and other cancers, how can we know what would have happened if their life expectancy were longer?

This is why epidemiological studies are highly suspect and are never used as proof, just for hypothesis generation. When curcumin was used in a randomized clinical trial with docetaxel, the trial was stopped early for futility:

clinicaltrials.gov/ct2/show...

There is no clinical evidence of efficacy, although there is some evidence that it masks PSA.

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"So, I called up the lab at which the study was done and asked to speak to the person who wrote the paper."

LOL, good for you. Please post any information you end up getting.

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I have been thinking about restarting Curcumin, and Reservatrol.

But I am wavering. When Dr. Sator took me off Avodart, he said all that can do is contribute to more mutation and evolution of the prostate cancer.

His implication being either hit the cancer with everything, or not at all. Doing anything in between threatens to make it stronger.

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I thought he and Dr. Myers had been in sync and avodart to lower dht was a mainstay of overall approach

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Yes, when in treatment mode.

But after the ADT, Myers kept me on low dose Avodart. Sartor took me off of it.

Myers accepted that as a valid alternative approach, at least in my case.

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What is the mechanism of the Ursolic Acid?

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Curious to know what folks use and think the best Ursolic acid supplement is. Also dosing determinations. Thanks.

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I would remind you guys that ursolic acid has the triterpenoid structure (similar to other steroids like testosterone, estrogen, and progesterone) but with an extra ring. It is known to be an aromatase inhibitor - which means it prevents testosterone from metabolizing into estrogen - leaving more T in the serum. There has never been a safety or efficacy study of it in humans. You may be causing your prostate cancer to grow.

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Those are all mouse/lab studies. Do you really think it applies to humans? Most mouse studies don't. If so, I've got a bridge to sell you. You can use yourself as a guinea pig, but don't drag others down with you. Why harm others?

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Tall_Allen - Do you take any supplements? I’m curious. I tend to air on the side of caution in this area too as I agree if everything that worked in nice worked in humans we’d be off to the races. But am I missing a no brainier that should be taken?

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I take no supplements. If I had advanced PC, I might take sulforaphane - at least there is a small randomized clinical trial proving efficacy and safety, and there is good biochemical reason that it might be useful.

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I think foods are fine (in moderation) - it is supplements I have an issue with. Our bodies didn't evolve to deal with large amount of chemicals in a supplement pill.

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I still say chocolate chip ice cream... (two scoops).... and don't leave any for the mice...F'em

Good Luck and Good Health.

j-o-h-n Wednesday 08/01/2018 7:42 PM EDT

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