Metformin and Prostate Cancer - Part Two: Recent Research / Clinical Results

[cujoe]

Part One, Metformin Anticancer Use - A Review of Current Evidence is here:

healthunlocked.com/fight-pr...

As many PCa patients already know, there is much clinical evidence of metformin being beneficial as an adjuvant to SOC. In fact many patients are currently using metformin, most often via a script written by their PCP. (Sometimes with the approval of their MO, sometimes without.) The original indications that metformin might be helpful were derived by statistical evidence that patients who had been taken metformin (usually for type 2 diabetes) had less incidence of PCa and less-aggressive cancer than those that were not. The following recent research articles look at some of the various potential uses and mechanisms involved in the utilization of metformin as an adjuvant PCa treatment.

1. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway

Highlights

• Combining of metformin and quercetin synergistically inhibit the viability, migration and invasion of prostate cancer cells.

• Metformin and quercetin synergistically induce apoptosis in a caspase-dependent way in prostate cancer cells.

• Metformin and quercetin synergistically inhibited the VEGF/PI3K/Akt signaling pathway in prostate cancer cells.

Abstract:

sciencedirect.com/science/a...

2. Metformin Use is Associated with Improved Survival for Patients with Advanced Prostate Cancer on Androgen Deprivation Therapy

Conclusions: Metformin use in veterans with prostate cancer who receive androgen deprivation therapy is associated with improved oncologic outcomes. This association should be evaluated in a prospective clinical trial.

Abstract:

pubmed.ncbi.nlm.nih.gov/299...

3. 1948P: Effect of docetaxel-resistance on the reactivity of prostate cancer cells to metformin

Conclusions: These data indicate that reactivity of drug-resistant prostate cancer cells to metformin may depend on the efficiency of metabolic stress-induced EMT. EMT-related metabolic elasticity that apparently increases invasive potential of PC3 cells in the absence of DCX may limit the application of metformin in therapy of drug-resistant prostate tumors.

Abstract:

sciencedirect.com/science/a...

4. Metformin inhibits the activation of melanocortin receptors 2 and 3 in vitro: A possible mechanism for its anti-androgenic and weight balancing effects in vivo? Note: While this research is not specific to PCa, MCR2 & MCR3 are both bad players in PCa. For more info, see here: (pdfs.semanticscholar.org/aa...

Highlights

• Metformin has mild anti-androgenic and weight lowering effects in clinics.

• Melanocortin receptors are involved in signaling systems controlling steroid production and weight.

• MC2R signaling targets androgen production.

• MC3R signaling seems important for regulating weight balance under stressful conditions.

• In a cell model, metformin inhibited ACTH-stimulated activity of MC2R and MC3R specifically.

sciencedirect.com/science/a...

5. Metformin and statins: a possible role in high-risk prostate cancer

Conclusion: Metformin and statins were not associated with BFFS or DFFS improvement in our analysis. However, the small number of patients treated with these drugs limits the reliability of the results and prospective studies are needed.

sciencedirect.com/science/a...

6. Metformin Anticancer mechanisms - Impact of metformin on immunological markers: Implication in its anti-tumor mechanism - Pre-pub proof to appear in Phamacology & Therapeutics, September 2020,

This paper addresses the use of metformin as an adjuvant to immunotherapy. While not currently a major treatment avenue for PCa, that will likely change over time. One interesting note is that the author suggests that metformin use may be contraindicated for immunocompromized individuals.

Abstract

Metformin, an anti-hyperglycemic drug, has been known to have antitumor properties for around 15 years. Although there are a number of reports attributing the antitumor function of metformin to its impact on energy homeostasis and oxygen re-distribution in tumor microenvironment, detailed mechanisms remain largely unknown. In the past several years, there is an increasing number of publications indicating that metformin can affect various immunological components including lymphocytes, macrophages, cytokines and several key immunological molecules in both human and animal studies. These interesting results appear to be in line with emerging data that suggest associations between immune responses and energy homeostasis/oxygen re-distribution, which may explain effective impacts of metformin on immunotherapies against autoimmune diseases as well as cancers. This review article is to analyse and discuss recent development in the above areas with aim to justify metformin as a new adjuvant for immunotherapy against human cancers. We hope that our summary will help to optimize the application of metformin for various types of human cancers.

Link for the Abstract

sciencedirect.com/science/a...

And the full paper via sci-hub:

sci-hub.tw/10.1016/j.pharmt...

Note: Full Papers are accessible via sci-hub.

Stay Safe/ Be Well - K9

PS I do not take metformin, but have been taking it's natural "equivalent", Berberine, for several years.

[jdm3]

Thanks. You're on a roll with all the research and it provides useful information to all of us.

I don't take metformin either and I'm wondering why I don't because many signs point to some benefit. I will add that I have heard metformin can cause some digestive discomfort and/or fatigue for some. Especially lean BMI folks without any metabolic issues. Finally, when I asked my MO a couple years ago he gave me his usual response and said "we don't prescribe it and some data suggest metformin may actually inhibit the efficacy of chemotherapy." So, as always, mixed signals, but lots of good studies beginning to tip the scales in favor of metformin.

[cujoe in reply to jdm3]

jdm3, Thanks for the input, esp., since it seems that I may be among the few 'lean BMI' people left in the Western world. Eons ago before I had (or maybe better stated, no knowledge of) any major health issues, I usually tested to the high side for glucose and for lipids. Based on my diet and a less-active lifestyle, it is not, in retrospect, very surprising. As for metformin vs berberine, I'll take a naturally derived "or equal" product over a synthesized one every time and, in the case of berberine, with the full realization that some or all of it's mechanisms of action may be different from it's pharma sibling.

According to Wiki:

Metformin was discovered in 1922.[15] French physician Jean Sterne began study in humans in the 1950s.[15] It was introduced as a medication in France in 1957 and the United States in 1995.[6][16] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[17] Metformin is the most widely used medication for diabetes taken by mouth.[15] It is available as a generic medication.[6] In the United States, it costs US$5 to US$25 per month.[6] In 2017, it was the fourth-most commonly prescribed medication in the United States, with more than 78 million prescriptions.[18][19]

So, it has been it widespread use for a long time - and in generic form is much less expensive than is berberine. That said I'm becoming more in agreement with Nassim Taleb's comments on drug interventions expressed in his book, Antifragile:

Second principle of iatrogenics: it is not linear. We should not take risks with near-healthy people; but we should take a lot, a lot more risks with those deemed in danger.

Why do we need to focus treatment on more serious cases, not marginal ones? Take this example showing nonlinearity (convexity). When hypertension is mild, say marginally higher than the zone accepted as “normotensive,” the chance of benefiting from a certain drug is close to 5.6 percent (only one person in eighteen benefit from the treatment). But when blood pressure is considered to be in the “high” or “severe” range, the chances of benefiting are now 26 and 72 percent, respectively (that is, one person in four and two persons out of three will benefit from the treatment). So the treatment benefits are convex to condition (the benefits rise disproportionally, in an accelerated manner). But consider that the iatrogenics should be constant for all categories! In the very ill condition, the benefits are large relative to iatrogenics; in the borderline one, they are small. This means that we need to focus on high-symptom conditions and ignore, I mean really ignore, other situations in which the patient is not very ill.

. . . Consider that Mother Nature had to have tinkered through selection in inverse proportion to the rarity of the condition. Of the hundred and twenty thousand drugs available today, I can hardly find a via positiva one that makes a healthy person unconditionally “better” (and if someone shows me one, I will be skeptical of yet-unseen side effects). Once in a while we come up with drugs that enhance performance, such as, say, steroids, only to discover what people in finance have known for a while: in a “mature”market there is no free lunch anymore, and what appears as a free lunch has a hidden risk. When you think you have found a free lunch, say, steroids or trans fat, something that helps the healthy without visible downside, it is most likely that there is a concealed trap somewhere. Actually, my days in trading, it was called a “sucker’s trade.”

Hope your garden and your first mate are doing equally well and both flourishing in the summer season. Regards, K9