Xtandi/Enzalutamide & Curcumin/Turmeric

[pjoshea13]

Is curcumin contraindicated while on Xtandi?

There have been a few recent posts on this subject. Rather than respond to them individually, I'm starting yet another thread. LOL

This is also a follow-up to an old post, which was a response to Cromone, who had been told to avoid curcumin, because:

"the Oncologist consulted the Pharmacist who suggested that I should stop the Curcumin as he was not familiar with Curcumin supplementation and was unsure of what, if any, inter-reaction their could be."

More recently, Daddysdaughter:

"My father is on Xtandi and he was told to stop taking tumeric because it decreases the effectiveness for the Xtandi.. he also was told to stop green tea."

Rexwaterbury responded:

"I am on Xtandi. Dr Myers also told me to stop turmeric."

I can't find any studies that support a contraindication.

Dr. Myers had positive things to say about curcumin in 2010:

askdrmyers.wordpress.com/20...

This video was re-posted on Sep 04, 2015, with the following comment:

"In the past few weeks we’ve received several questions about curcumin. So, this week we’re re-running a video Dr. Myers prepared about curcumin back in 2010."

But in the 2 years before retirement, Dr. Myers seems to have found reason to suspect an interaction.

...

Xtandi [Enzalutamide, MDV3100] is a nonsteroidal antiandrogen. It binds to the androgen receptor [AR], but unlike Casodex, the AR does not translocate to the nucleus. Also unlike Casodex, Xtandi remains an AR antagonist (Casodex can eventually become an agonist for mutant AR).

{Dihydrotestosterone [DHT] (the natural AR ligand) strongly competes with Xtandi for AR binding, so it is just as well to use Avodart, even with castrate testosterone [T], since PCa has been known to manufacture DHT via a back-door path that does not involve T.}

Curcumin does not bind to the AR, so does not compete with Xtandi.

Curcumin does, however, target the AR. Why might that be a problem? Seems that there might be synergy with Xtandi. The team behind the following study (2016) [1] clearly think so:

{Note: ASC-J9(® is a synthetic curcumin analog with greater bioavailability.}

"The detailed mechanisms how CRPC develops Enz {Enzalutamide - Xtandi} resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L."

A 2002 paper first reported curcumin-related AR activity [2]:

"... curcumin has a potential therapeutic effect on prostate cancer cells through down-regulation of AR and AR-related cofactors (AP-1, NF-kappaB and CBP)."

The following is from a full-text review of curcumin & PCa [3]:

"Uncontrolled AR gene amplification, AR mutations, and increase of AR expression appear to be a selective driving force for the progression of prostate cancer to the hormone refractory state. Curcumin was shown to have an influence on the expression level of typical prostate marker proteins. In fact, in response to curcumin treatment, the AR expression was strikingly down-regulated as well as the AR binding activity to the androgen response element of the prostate-specific antigen protein (PSA) gene, and the PSA expression in LNCaP cells. This phenomenon is expected to deprive these cells of a critical growth advantage and classifies thus this phytochemical as a non-toxic approach to the management of AR-dependent prostate cancer"

In 2013, the ASC-J9(® people [4]:

"examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 μm Casodex or MDV3100 {Xtandi} treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models."

Which suggests to me that curcumin + Xtandi might be a good partnership, provided that the curcumin used was truly bioavailable (most products are not - turmeric certainly isn't).

Also in 2013 [5]:

"Here we found that ADT with the currently used Casodex (bicalutamide) and the newly developed MDV3100 (enzalutamide) promoted PCa metastasis via enhancing macrophage infiltration in both in vitro co-culture systems and in vivo mouse models. In contrast, the newly developed AR degradation enhancer ASC-J9 showed an opposite effect, suppressing the macrophage infiltration and consequent PCa metastasis."

...

"Enzalutamide is a moderate to strong inducer of multiple cytochrome P450 enzymes including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions." [6] i.e. greater clearance & reduced effectiveness.

That is certainly a problem when using supplements with poor bioavailability due to CYP3A4 clearance. Adding piperine might help, but one would need to start with a good curcumin product, such as LongVida (CurcuBrain).

...

Obviously, I haven't answered the question. {The answer is not to be found on PubMed.} There seems to be a good case for curcumin use to degrade up-regulated AR. Unfortunately, Xtandi might accelerate clearance of curcumin. Given the poor availability of most curcumin products, it's difficult to visualize curcumin getting in the way of Xtandi.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/272...

[2] ncbi.nlm.nih.gov/pubmed/122...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] jbc.org/content/288/27/1935...

[5] ncbi.nlm.nih.gov/pmc/articl...

[6] en.wikipedia.org/wiki/Enzal...

[cesanon]

Patrick, do you have any positive or negative thoughts on Curcumin/Turmeric for those not taking Xtandi?

[pjoshea13 in reply to cesanon]

Cesanon,

I take curcumin & would continue even while on Xtandi, in the absence of a sound reason not to.

I think that turmeric would not be very useful, unless one were to drink strong turmeric tea throughout the day.

As with resveratrol, it is best to avoid cheap supplements with poor bioavailability. I'm not saying that LongVida (CurcuBrain) is the best choice, but most products have not solved the bio-unavailability issue, so caution is required.

-Patrick

[Daddysdaughter in reply to pjoshea13]

So you recommend curcubrain?

[Daddysdaughter]

So it’s ineffective because it gets cleared faster with Xtandi. So really taking it doesn’t decrease the the effectiveness of Xtandi or cause any severe side effects.. i just honestly feel that his PSA stayed lower when he was on tumeric. But it could just be coincidental.

[Kuanyin]

For what it is worth, the original ASC-J9AR degradation enhancer,antiumor agent mentioned in the research paper is available at APExBIO. For some reason, the URL is too large to fit conveniently into this space." APExBIO will get you there."

[Daddysdaughter in reply to Kuanyin]

It’s an Epigenetics site

[bdriggers]

My Primary is stubbornly against supplements, including turmeric. Currently he has me on D3 plus K and B12, since I gave up red meat. I think he is like you said, unsure of interactions if any.

[Daddysdaughter in reply to bdriggers]

I have heard B12 increases cancer growth. Personally i have not researched for my father but a colleague of mine that is very knowledgeable on supplements and vitamin told me to have my father avoid it.

[pjoshea13 in reply to Daddysdaughter]

IMO, B12 insufficiency is PCa-protective. -Patrick

[EdBar]

I started seeing Dr. Myers in 2015 and Curcumin was one of the supplements he recommended. During my last consult with him in September he said I could stop it if I want but did not direct me to. I've been taking Xtandi since 2015 and my PSA has remained undetectable. I still have a supply of Curcumin left so I continue to take it. During my recent visit with Dr. Sartor, Snuffys replacement he had no problem with taking Curcumin when he reviewed my supplements. It may or may not help, it doesn't seem to hurt so for me if it works don't fix it.

Ed

[Daddysdaughter in reply to EdBar]

That is great to know! Thank you! Do you take a more bioavailabe curcumin

[EdBar in reply to Daddysdaughter]

I take the one that Snuffy recommended which is Jarrow Formula (brand name) 500mg available on Amazon

[pjoshea13 in reply to EdBar]

Ed,

That's useful info.

Thanks, -Patrick

[podsart in reply to EdBar]

Ed

Interesting, I also am a former Dr Myers patient and was put on life extension curcumin when I first saw him in 2011 and he never changed this. I also last saw Dr Myers in September.

Further, I have been on Xtandi since 2/16 and it immediately dropped PSA to undetectable

I wonder why he didn’t switch me to that Jarrow product.

Ps when I tried going to that APExBIO using google search get to site where can buy various products, any other way to get to the correct url?

[EdBar in reply to podsart]

Life extension is another brand of supplement that Snuffy held in high regard. I use LE for a couple of other supplements that he has/had me taking. Who are you using in place of Snuffy?

Ed

[podsart in reply to EdBar]

Ed

He referred me to Dr Drake--I live in NY

Forgot, where do you live?

Trying to assemble the list that Dr Myers used to refer people to

Dr. Sartor,Dr Sholz, Dr Drake, Dr Farrara? Others, anyone?

[EdBar in reply to podsart]

I live in the Atlanta area so Sartor in NOLA is not that far away for me.

[podsart in reply to EdBar]

Thanks

[Daddysdaughter in reply to podsart]

I just called Dr. Mark Scholz Southern California and he does not accept Medicare-cal

[podsart in reply to Daddysdaughter]

That’s a problem; likely doesn’t accept my Medicare NY and unitedhealthcare

[Daddysdaughter in reply to podsart]

He might accept United. Call and ask. I believe the application is online.

[pjoshea13 in reply to EdBar]

I am a LEF member. I use their 7,000 IU vitamin D caps. I am generally a big fan, but their Super Bio-Curcumin® is only "7 times more absorbable than conventional curcumin supplements". That hasn't changed in years & it's not good enough when we have several better options.

I favor LongVida (CurcuBrain), but Anthony from RevGenetics says that his product meets Dr. Myers criteria (as discussed some years back).

-Patrick

[cesanon in reply to podsart]

Ed same story here. Here never changed me from Life extension. But a few years ago he said not to bother with the curcumin at all. That the metformin was good enough.

[Daddysdaughter in reply to podsart]

I found that Jarrow is a probiotic formula.

[Daddysdaughter in reply to Daddysdaughter]

I found it! On life extension website - which curcumin formula did Snuffy recommend?

[podsart in reply to Daddysdaughter]

Supper bio curcumin 400mg. 3 per day

[podsart in reply to Daddysdaughter]

Which jarrow curcumin product there are 2?

Where did u find info re it is probiotic ?

[Daddysdaughter in reply to podsart]

I had gone directly to their site and only saw probiotics but it could have been my phone.

[chascri]

Thanks again Patrick for your timely analysis.

[Daddysdaughter]

I just spoke with PA in regards to tumeric, she said that the oncologist does not recommend taking it because of P450 metabolism? She mentioned that it might make Xtandi go to toxic levels

[pjoshea13 in reply to Daddysdaughter]

And yet:

"There is low potential for CYP450 mediated drug interactions at physiologic serum concentrations of liposomal curcumin. Based on preliminary data, liposomal curcumin will not interact with other chemotherapy agents that are metabolized and/or eliminated via the primary drug metabolizing CYP450 pathways."

ncbi.nlm.nih.gov/pubmed/203...

-Patrick

[Magnus1964]

I am on an xtandi drug trial. I will ask my research team about turmeric and curcumin and get back to the group.

[podsart]

Nalakrats

What’s your view of curcumin and Xtandi, including the CYP450 issue?