"Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance."
"We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT."
"These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy ..."
Cell Death Dis. 2017 Aug 24;8(8):e3007. doi: 10.1038/cddis.2017.417.
Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.
Liu Q1, Tong D1, Liu G1, Xu J1, Do K2, Geary K2, Zhang D2, Zhang J1, Zhang Y1, Li Y1, Bi G1, Lan W1, Jiang J1.
Author information
1
Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
2
Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA.
Abstract
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-β1, we propose that metformin exerts its effects by targeting the TGF-β1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.
PMID: 28837141 DOI: 10.1038/cddis.2017.417
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I can,t find where it states 4 x 500mg. in the literature. With my A1c at 5.8, I am concerned my glucose level would fall too low with 2000 mg of metformin per day. What about a lower dosage like 1000 mg. divided into 2 doses?
Previous to your e-mail, I thought that was the only option to prevent a hypoglycemic event. I will have to test my blood surgar, but I think it is worth it to extend the duration of Zytiga. Another research study showed this action for Zytiga, too.
My dad has been on 1000mg of Metformin, for 2 years now, under Dr. Myers' guidance. He said 1000mg has therapeutic effect as well, and the longer it is used, the more it can positively change the cancer micro-enviornment, thus possible changing the course of the disease into a less aggressive state (at least that's the summary I wrote in my notes).
Thanks for this new info, we'll share it with my dad's new oncologist (who also supports taking Metformin, for metabolic syndrome reasons, but I suspect there's increasing realization among some oncologists that the drug does indeed have a subtle therapeutic effect on PC cells.
Thanks for your comment and all of the good work you are doing for so many people with your many posts. I am continually reviewing much of your work on HU and finding it extremely useful!
Dr. Myers sure was right about Metformin. He also said Metformin made PCa less aggressive over time..I wonder what effect Metformin has in preventing resistance to Lupron
I agree with Nalakrats & Tarhoosier. Dr. Myers has noted that the benefit seems to increase with the length of use. Start Now.
You might not get the full dose of 4 x 500mg. There is a waryness because some have intestinal upset with it. My original script, years ago, was for 2 pills daily, & my pharmacist advised me to start with one/day for two weeks. I never had a problem & now take two pills each, with the two biggest meals of the day.
Thanks for posting the article. However, these outcomes for Metformin don't seem to be exactly new, at least according to other articles. Our oncologists must have been aware of the problem with Xtandi and its possible solution (for awhile, anyway) with Metformin. Certainly Dr Meyers was aware of the interaction between these two medications, since he was advising his patients to take Metformin. The implications of this seeming failure, at worst, or reluctance, at best, of oncologists (at least the ones I have spoken with) to discuss taking Metformin while on Xtandi should be of concern to all of us.
I could never tolerate "regular" Metformin, no matter how I titrated it: sometimes, my stomach was fine, other times, however, it was really painful, no matter how large the meal. My solution has been to take Mylan Metformin Osmotic ER. Never had a problem with it.
"We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT." No mention of AR-V7.
The finding on protection against AR-V7 is old.
It's comforting to know that Metformin may protect via multiple mechanisms.
-Patrick
Good post.
• in reply to
""We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT."
That is unexpected. Preventing the epithelial to mesenchymal transition.
How is that related to resistance to enzalutimide? What is the connection?
Hindering resistance usually is thought of as a delay in the appearance of the splice variants. How much is known about EMT? I don't know much/anything about that.
Thank you. I've been aware of Dr, Myers fondness of metformin for quite sometime and have asked my MO about it several times. However, until now, he says he has not seen clinical studies/evidence of the actual benefit.
I've put it (adding Metformin) on the back burner because I was pushing for an AUS and Provenge.
Well, I had the AUS implant in May and completed Provenge 2 weeks ago. I'll share this new info and begin pushing hard.
"Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance."
Patrick, I read most of that, did not understand that much, but I am very glad to know, they are working on what causes resistance , I think that may be the key to long term chronic disease management of CRPC.
Thanks for the paper, I will defitely ask for a CTC test to test for arv7 over-expression.
Hello everyone, I am taking Xtendi 140 mg with a 1000 mg of Metformin, and its working great for me, my PRimary physician it’s all for it, she had told me of that study and recommended. The last 11 months of this therapy my PSA it’s been 0.01. I will stay on it until. Just taking one day at the time.
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