I just came across this article that seems to suggest PC cells develop resistance to metformin after "long term use" which can be reversed by withholding metformin for 30 days:
>Metformin resistance was suggested to be associated with transcriptional programs that may induce reversible cell cycle arrest. Our clone formation assay showed that MetR cells restored metformin sensitivity after thirty days of drug withdrawal (Fig. 1e, f), for example, the proliferation rate of these MetR cells eventually became similar to that of wild-type (WT) cells. These results indicated that metformin resistance in PCa cells is likely to be a transient phenotype. This is in agreement with previous studies, which indicated that metformin resistance may be associated with reversible cell cycle arrest.
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I just spent "an hour or two" looking up the latest research on metformin and metastatic prostate cancer and adding the search term "RCT". I was interested to see (my own interpretations) that (a) "metformin as adjunct therapy against metastatic prostate cancer progression" is the subject of a lot of interest; (b) there are however some studies which show no effect, including secondary data analysis studies based on the big PCa RCTs; (c) I didn't see any studies that show that it would be a sad mistake to take metformin; (d) there is a lot of call for RCTs on the topic; and (e) on the theory that absence of evidence is not evidence of absence, there does seem to be some reasonable theorization that metformin could be helpful.I'm taking it because have metabolic syndrome depending on what I ate this week.
No. Read the article. You don't understand how to evaluate research, which could be harmful to your health. The latest higher level of evidence data (MAST) show that men with high BMI had increased progression with metformin, and a randomized trial showed that drugs that reduce metabolic syndrome in diabetics do not reduce metabolic syndrome among ADT users.
It's a good encouragement for anyone to be careful about self-medication and misinterpretation of research that is intended for professionals. To reword that old cliche about lawyers, anybody who pretends to be their own doctor has a fool for a client.
However, in this case I saw both the points you made. And neither one of them apply to myself.
1) My BMI is not bad.
2) I'm not diabetic, even if I have metabolic syndrome.
3) I'm interested in the possible efficacy of metformin off-label against metastatic prostate cancer. Nothing I read showed definitively that metformin does not work as I would like it to.
4) And nothing I read showed increased risk, as I don't have high BMI.
Doctors can be fools too. As I have shared when I was diagnosed over two years ago now with de novo high volume metastatic prostate cancer - because of a backache - which was revealed to have compromised three of my vertebrae - and my PSA was 1700 - it became clear to me that being informed is worthwhile.
My doctor was against PSA testing. An annual DRE is a poor diagnostic. Me and an increasing number of men are diagnosed with prostate cancer where metastasis has already happened.
3) We await STAMPEDE, which will be definitive. But the highest level of evidence so far, and across multiple Level 2 trials, consistently shows no benefit. This RCT shows no benefit wrt metabolic syndrome in non-diabetic men who are taking ADT:
4) The large MA.32 RCT in women with breast cancer proved there werestatistically significant increases in serious (Grade 3) toxicities among those taking metformin vs placebo: 21.5% vs 17.5%, respectively.
In a secondary analysis of two randomized clinical trial databases, there were 486 patients treated with radiation and ADT. Follow-up was over 10 years. 10-year biochemical recurrence-free survival was:
•73% if they used metformin
•85% if they did not use metformin
• The adjusted hazard ratio was 2.11 (over twice as bad for metformin users)
Metformin was associated with inferior biochemical outcomes.
While metformin does not have serious side effects in most men, it does commonly have gastrointestinal side effects (diarrhea, cramps, nausea, vomiting, and flatulence). It should be avoided in men with known contraindications: lactic acidosis, metabolic acidosis, poor liver or kidney function, and hypoglycemia. There are many drug/supplement interactions that should be carefully checked.
In a secondary analysis of two randomized clinical trial databases, there were 486 patients treated with radiation and ADT. Follow-up was over 10 years. 10-year biochemical recurrence-free survival was:
85% if they used metformin
73% if they did not use metformin
Metformin was associated with inferior biochemical outcomes.
Pasted from the link, which was confusing, just thought to bring it to your attention:
Possible Metformin Danger
In a secondary analysis of two randomized clinical trial databases, there were 486 patients treated with radiation and ADT. Follow-up was over 10 years. 10-year biochemical recurrence-free survival was:
85% if they used metformin
73% if they did not use metformin
Metformin was associated with inferior biochemical outcomes.
My situation is similar to yours in that I am slim and nevertheless have metabolic syndrome.
However rather than Metformin, I take Berberine which is similar in effect but apparently has a safer profile that Metformin regarding the impact on vitamin B12 and magnesium absorption levels.
Metformin works by reducing the liver’s ability to release glucose and inhibiting glucose absorption from the intestines.
Berberine is an herbal supplement that you can buy over the counter. It activates AMP-activated protein kinase (AMPK), which helps regulate metabolism and blood sugar levels.
While Berberine offers benefits for blood sugar control, it has an antibacterial action that seems to remove the harmful bacteria in the gut and enhance the growth of healthy bacteria
I am not certain it helps against prostate cancer but it helps in metabolizing glucose and is beneficial for longevity, metabolic health, weight loss, and more so that makes it worth it in itself for me.
Hey Mascouche, I appreciate your note. I'm also taking berberine although I don't talk about it so much 😃. So I'm taking both berberine and metformin. I really hope this is a good idea.
To take any supplement or off label med is a huge responsibility. From your notes you are clearly knowledgeable. I made a list once of things to worry about when you take a supplement. I came up with a list of I think 60 things to worry about, including for example likelihood of manufacturing contamination. (This is not a commercial post but I do like the Natural Factors people out of British Columbia for supplements.)
I have even stopped taking a supplement after ongoing reading reveal the concern. There is lots of positive information encouraging one to take Taurine. But I stopped taking it because I read something that was concerning in relation to metastatic prostate cancer.
Of course the most important adjunct therapy for PCA is exercise, both aerobic and resistance exercises! I was doing really great on this until I started the job part time about 2 months ago. If you ask me I'd prefer not to answer as to how well I'm doing on my exercise now!
I understand JohnInTheMiddle and I agree that one has to be carefull about so many things such as info, sources, etc... Even things we once thought we knew. I used to do lots of long water fasting because the autophagy it triggers is supposed to protect against getting cancer. But several months ago, I've learned that once you ALREADY have cancer, than autophagy can help the creation of metastases, I was stunned.
Suddenly something you were convinced would benefit you turns out to play against you because the rules are not the same when you already have cancer.
I’ve been taking Metformin for about 10 years now per Snuffy Myers, I’ve maintained normal BMI despite long term ADT (along with proper diet and exercise). It remains part of my treatment regiment and will continue to do so, despite the naysayers, if it works don’t fix it. It’s cheap, low or no side effect drug that’s been around forever with a long safety record.
Thanks Ed! And also thanks for reminding me about one of my original motivations for going on metformin, which was to help keep ADT driven weight gain down.
I'm guilty of mostly thinking about possible benefits of metformin as adjunct PCA therapy. And I'm becoming aware that this is not a straightforward proposition. So far I haven't seen anything that makes me concerned that metformin would actually make the situation worse.
But maintaining a level of fitness while on long-term ADT is so important. Apparently up to 1/3 of metastatic prostate cancer deaths are due to therapy associated cardiovascular disease!
And to you also! And metformin may just have some anti cancer properties as well. Snuffy was big on a multidimensional approach and metformin was part of that. 10 years and I’m still on the Snuffy treatment program, I’m not changing a thing.
Ya I don’t pay too much attention to those, I don’t think any of those studies combined Metformin with other treatments. Lupron, Xtandi Avodart, early chemo, Provenge, debulking the prostate etc. For me these were/are all part of a multidimensional approach - hit it hard from different pathways. If I’d listened to all the naysayers early on I probably wouldn’t be here today. And I don’t want to forget the power of prayer probably the most important treatment. Much of the guidance I’ve received has come from prayer.
So what do you think about the possibility of metformin resistance? Do you think there's a downside to discontinuing it for 30 days after long term use?
I have no idea about metformin resistance. And if I did it would be unfounded.
Was it you that posted the article recently about metformin resistance? It sounded plausible to me. And I was very interested in fact.
It almost sounded like BAT for metformin. I'm not actually that interested in BAT but I haven't seen anything that says it works really well.
I've only been on metformin a year; I don't know how I'd know if I had developed metformin resistance, whatever that is. But hey stopping for a month? To resensitize? Could be a good idea?
One thing I noticed about talking about this is the levels of complexity that we are dealing with here. The recent discussions here about metformin have highlighted our lack of knowledge.
And now we're talking about whether or not metformin resistance is a thing and whether a hiatus might resensitize. The uncertainties and probabilities and unknowns really start to add up.
Yes, I originally posted the article referencing metformin resistance. I agree that metformin use is clearly not a yes it works/no it doesn't work answer.
It looks like the majority of the studies in TA's article apparently show no benefit after years of follow up. One study showed some patients benefited after 8 weeks but not long term. Could that possibly be due in part to resistance? I think it's worth considering.
Unfortunately I couldn't find what they considered "long term" use.
I am thinking the downside of stopping metformin for 30 days periodically would be minimal for those who are taking it. Just wanted to hear what others thought.
Thanks so much DS starting this important discussion. I think your conclusions are excellent. And we acknowledge that there's lots of uncertainty here. I'm continuing to take metformin and will now consider if I should take a break once in awhile. FYI I'm also taking berberine, which is you may know might be complimentary to metformin. I continue to review the small number of supplements I take. And because of such review I stopped taking taurine.
>Conclusions: Taurine promoted apoptosis and inhibited proliferation of prostate cancer cells, and its mechanism of action may be related to the MST1/Hippo signaling pathway in a dose-dependent manner.
Here's a study that suggests that metformin can provide a benefit against prostate cancer progression. Careful with your usual misleading blanket misstatement about 'best evidence'.
It is only subjective among those who willfully ignore the hermeneutics of medical science. You can read about levels of evidence at the link below if you are want to. All medical researchers abide by them:
From the Prince of darkness "A" and the Princess of light "i".
Development of metformin resistance in Prostate cancer cells after long-term treatment
ChatGPT
Metformin, a widely used drug for the treatment of type 2 diabetes, has been investigated for its potential anti-cancer properties, including in prostate cancer. However, like many treatments, there is a possibility that cancer cells can develop resistance to metformin over long-term use. Here's an overview of the development of metformin resistance in prostate cancer cells and potential strategies to overcome it:
Mechanisms of Metformin Resistance in Prostate Cancer Cells
Alterations in Metabolic Pathways:
Cancer cells are highly adaptable and can modify their metabolic pathways to bypass the effects of metformin, which targets cellular metabolism.
Genetic and Epigenetic Changes:
Prostate cancer cells may undergo genetic mutations or epigenetic modifications that reduce the drug's efficacy. These changes can affect key regulators of cell proliferation and survival.
Activation of Compensatory Pathways:
Cancer cells might activate alternative signaling pathways that allow them to survive despite the presence of metformin. For example, upregulation of the PI3K/Akt/mTOR pathway can contribute to resistance.
Drug Efflux Mechanisms:
Increased expression of drug efflux pumps can reduce the intracellular concentration of metformin, diminishing its anti-cancer effects.
Changes in AMPK Activation:
Metformin primarily exerts its effects by activating AMP-activated protein kinase (AMPK), which inhibits mTOR signaling. Alterations in AMPK activation can lead to resistance.
Research on Metformin Resistance
Studies have shown that long-term exposure to metformin can lead to the development of resistance in various cancer cell lines, including prostate cancer. Research in this area aims to understand the underlying mechanisms and find ways to prevent or overcome resistance.
Strategies to Overcome Metformin Resistance
Combination Therapy:
Combining metformin with other therapeutic agents can enhance its efficacy and prevent resistance. For example, combining metformin with PI3K/Akt/mTOR inhibitors, anti-androgens, or other metabolic inhibitors has shown promise in preclinical studies.
Targeting Compensatory Pathways:
Inhibiting the alternative pathways that cancer cells use to escape the effects of metformin can help overcome resistance. Drugs that target these compensatory mechanisms can be used in combination with metformin.
Epigenetic Modifiers:
Using drugs that target epigenetic modifications, such as DNA methyltransferase inhibitors or histone deacetylase inhibitors, may reverse resistance by restoring the sensitivity of cancer cells to metformin.
Novel Metformin Derivatives:
Developing new derivatives of metformin that have improved anti-cancer properties or can evade resistance mechanisms is another potential approach.
Personalized Medicine:
Tailoring treatment based on the genetic and molecular profile of the patient's tumor can help identify those who are likely to benefit from metformin and those who might develop resistance.
Conclusion
While metformin has shown potential as an anti-cancer agent in prostate cancer, the development of resistance remains a challenge. Understanding the mechanisms of resistance and developing strategies to counteract it are crucial for enhancing the efficacy of metformin in cancer therapy. Combination therapies, targeting compensatory pathways, and personalized treatment approaches are promising strategies to overcome metformin resistance in prostate cancer cells. Ongoing research is essential to further elucidate these mechanisms and translate these findings into clinical practice.
john -AI is a great tool, but it doesn't know what is important and what isn't unless it also learns that. It could be more useful if it somehow learns how to evaluate level of evidence and GRADE. It could conceivably do that, but you would have to guide it in learning those principles. Teaching it statistics might improve it too.
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