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September 3, 2010
Metformin Against Cancer?
Posted by Derek
It's always good to hear about an older compound that may be doing good things that we didn't realize. The current example is metformin, the diabetes drug known to many by its brand name Glucophage, but a generic compound for some years now. Evidence has recently been accumulating that patients taking it over the long term may well have lower incidence of several types of cancer, which is a refreshing change from the usual creeping realizations in this business. (There's a reason for that - the opportunities to mess something up inside a cell, something you probably didn't even know was there, are far, far, more numerous than the opportunities to make something work the way you want).
A new paper may well have tracked down a mechanism for this effect, which adds to the sense that it's real. Here's a summary of the work - it looks like an mTOR-driven process, which is plausible. Specifically, it seems to inhibit the TORC1 pathway, though at least two different mechanisms. That's an important player in nutrient sensing and cellular growth, among a bewildering variety of other things, and the whole mTOR area has been the subject of oncology research for quite a long time now.
Metformin (and related biguanides) might be acting on it in a very useful way. Mice exposed to a known lung-cancer agent were substantially protected by pretreatment with the drug. What's not clear yet is if that direct TORC1 effect is the reason, or if it's a more general downstream effect having to do with metformin's effects on glucose levels and insulin signaling. If it's the latter, there are tumor lines that should (unfortunately) be able to evade the problem, specifically ones that have their PI3K signaling cranked up already, so it's going to be quite interesting to see how metformin does protecting against those. As has been noted many times, nutrient sensing, insulin signaling pathways, carcinogenesis, and mechanisms of aging are tangled together in ways that it's very much in our interest to unravel. (mTOR specifically is right in the middle of it, apparently).
These results (both the new mechanistic study in mice and the retrospective clinical observations) would seem to strongly suggest trying metformin out in patients with a high risk of developing various sorts of cancer. It also suggests that, other things being equal, Type II diabetics might want to use metformin to take advantage of its apparent side benefits. A protective effect would be very welcome news indeed - it's terribly difficult to do anything about most tumors once they've occurred, and the best thing would be for them not to appear in the first place.
Oh, and one more thing. If everyone had followed Sidney Wolfe's advice when metformin first came out - not to use it - we wouldn't have found out about these effects at all. Would we?
Comments (22)
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1. Aspirin on September 3, 2010 8:16 AM writes...
Aren't you a little skeptical that mTOR is being implicated in almost every disease process as a possible drug target these days?
Permalink to Comment2. Andy on September 3, 2010 8:53 AM writes...
A noteworthy practical difficulty is that compliance with proactive preventive medicine regimens tends to be sketchy. People need to actually be sick to be motivated enough to do something. Even in the context of preventing recurrence, compliance is problematic. It's much more straightforward to come up with treatments for people that are already sick.
Permalink to Comment3. peej on September 3, 2010 9:37 AM writes...
Nice work with the Sidney Wolfe reference. Notably, the part of the book where he classifies metformin as a "DO NOT USE" drug is not available on Amazon.
Metformin is now the hands-down favorite these days as a first line therapy for any type 2 diabetes, amd there is considerable evidence building that it may be useful in decreasing cardiovascular events too.
Permalink to Comment4. Kent G. Budge on September 3, 2010 10:42 AM writes...
Some time back I discovered that there is a community of persons taking Metformin off-label as "life prolongation drug." Well, if you're going to do something as questionable as that, it appears there are a lot worse choices than Metformin. Still.
Permalink to Comment5. DT on September 3, 2010 11:54 AM writes...
mTOR is quite a popular target, however I believe it is the downstream targets that people need to be looking at for various diseases.
Permalink to Comment6. Mike Burns on September 3, 2010 12:09 PM writes...
Metformin is a Caloric Restriction mimetic, and provides the benefits associated with the practice of Caloric Restriction, including increased insulin sensitivity, reduced insulin levels, and the upregulation of the energy sensing AMPK. This downregulates mTor. Its awesome multi-billion-man-year safety record, its protection against cancers, and potential for providing longer and healthier lives should goose the medical establishment towards making this an OTC preparation, and getting it into the hands of everybody over 40.
Permalink to Comment7. RM on September 3, 2010 12:48 PM writes...
I don't fully understand the last paragraph. Is there a deeper commentary there on the nature of assessing drugs on a personal level, and which of the many drugs for condition X is the best on the terms of cost/benefit tradeoff, or is it simply a pot-shot at Sidney Wolfe? (I'll admit that I'm not familiar with Wolfe or his book.)
Permalink to Comment8. ronathan richardson on September 3, 2010 5:49 PM writes...
Where's the reference to this post? http://pipeline.corante.com/archives/2009/02/26/does_glucophage_make_alzheimers_worse.php
You know, the one where you look at evidence saying metformin can promote alzheimer's.
Permalink to Comment9. Anonymous on September 3, 2010 8:29 PM writes...
Mike Burns #6 has some very important insight and is spot on. I've worked in the met. disease med chem area for many years and agree with his assesment. Although AMPK has been implicated in the MOA (mode of action) of metformin, it's still appears that metformin is a somewhat promiscuous drug that made it to market because of its safety profile. If you listen to the GSK blog, lipohpilicity imparts toxicity and so stay away from aromatic rings. They have a point there in this regard. This is the perfect drug, well established, hydrophilic, low MW however somewhat "black box" in it's MOA. It's ADME properties are perfect. Oral bio. = 50-60% and is excreted unchanged in the urine (yes, no metabolism!). I agree that this may be an important finding for the oncology arena.
Perhap's repositioning of this drug could provide significant benefit for cancer patients. Unfortunately, that wouldn't be a cash cow for pharma companies and so it is likely to stay way below the radar. Therefore the people need to step up and push the cause...
Permalink to Comment10. metaphysician on September 4, 2010 12:04 PM writes...
#9-
Why wouldn't it be a cash cow? After all, its an already proven safe drug, so if you can establish efficacy, your good. And even one linkage between improved cancer tolerance and metformin would probably result in a bunch of off-label usage.
Permalink to Comment11. Chucky on September 4, 2010 4:26 PM writes...
A couple problems with metformin are liver tox issues (elevated enzymes) and very rare lactic acidosis. It is an interesting drug and is very useful as a type 2 diabetes drug. To the extent that much of the Western World's health problems relate towards overeating and obesity, metformin appears to be a very nice complement.
Permalink to Comment12. Anonymous on September 4, 2010 8:32 PM writes...
@#10 metformin is now generic. BMS missed the boat! If one could somehow get a method of use patent on metformin for cancer then you will make cash. There will likely be a lot of push back (pharma co's mainly) to market a dirt cheap anticancer drug...and if that's the case, you might probably see the price of metformin prescriptions rise significantly. Is that what we all want??
Permalink to Comment13. Anonymous on September 4, 2010 9:28 PM writes...
Remember Metformin is a basic compound. How about a metformin salt (1:1 or 2:1 ) with a known cancer agent that is acidic. This makes sense. An inherant "combined therapy" . Anyone have any knowledge of any acidic cancer drugs??
Permalink to Comment14. dearieme on September 6, 2010 3:09 AM writes...
A different diabetes drug seems likely to have a different fate.
Permalink to Commenthttp://www.independent.co.uk/life-style/health-and-families/health-news/diabetes-drug-with-heart-attack-link-should-never-have-been-issued-2071275.html
15. Kismet on September 6, 2010 3:33 PM writes...
@11: IIRC recent evidence suggests that metformin does not promote lactic acidosis (at least in the studied group). I think this warning is outdated.
@6: metformin is only a CR mimetic if you use the term very broadly (then exercise may also be one!) It does not to replicate the key effects of CR in vivo: retardation of aging and thus extension of life span.
@1: that would not be surprising if you think about it. "caloric restriction" can prevent or retard basically all diseases in rodent models and its old news already.
Why? Of course because it retards aging.
Decreased mTOR signalling also does that (recent publication about rapamycin)
Of course that does not make mTOR or aging an easy target, but their potential is extraordinary.
Permalink to Comment16. partial agonist on September 7, 2010 7:05 AM writes...
Kismet, metformin produces lactic acidosis in patients with compromised renal function:
www-dot-medscape-dot-com/viewarticle/714920
Permalink to Comment17. Kismet on September 8, 2010 11:08 AM writes...
I was thinking of this article:
"The Phantom of Lactic Acidosis due to Metformin in Patients With Diabetes"
implying that the risk is exaggerated.
Of course, you could be right about this sub-group, as the authors wrote:
"Among the first million patients (approximately) to have received metformin in the U.S., there were 47 reports (20 fatal) to the FDA of lactic acidosis. Of these patients, 43 had renal failure (labeled contraindication for metformin [!]) or risk factors for lactic acidosis besides metformin (primarily congestive heart failure)"
Permalink to Comment18. Jesse on September 10, 2010 3:31 AM writes...
One possible stumbling block -- depression as one of the potential side effects of Metformin.
Ketamine is a drug with interesting anti-depressant activity, and one finding is that its action involves activating the mTOR pathway. For drugs which downregulate mTOR, depression and mood problems may turn out to be a general class feature.
Permalink to Comment19. suzy on November 13, 2011 1:43 PM writes...
Hurray! I read about Metformin and cancer in a Google alert on ovarian cancer cures. Since I am fairly diabetic (110) I take metformin, 850 mg daily. these last 8 months. A have ovarian cancer, had a few chemo courses and am about to start on Gemzar. Feel OK, no pains at all - never had - but in panic. Gemzar will probably stop my normal life for months. Now, maybe it's metformin that makes me feel so well despite the tumors inside? Should I take more for effect?
Permalink to CommentThank you.
20. Ruddie on January 18, 2012 1:24 PM writes...
what about metformin side effects? Sucanon is a new herbally based medication, clinical test show no adverse effects.
Permalink to Comment21. Ruddie on January 18, 2012 1:24 PM writes...
what about metformin side effects? Sucanon is a new herbally based medication, clinical test show no adverse effects.
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