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Metformin for Cancer

My interest for Metformin started with its use to enhance fertility (one of my practice interests) and led more recently to its potential use in cancer (my other practice interest).

Metformin is a diabetes medicine which originates interestingly from the French Lilac (Galega officinalis) plant (herbal medicine is my other interest!).  First described in 1957, it is one of the safest and most commonly prescribed drug for diabetes treatment in the world.

Metformin’s many physiologic actions include suppressing liver’s own sugar production (”hepatic gluconeogenesis”), increasing insulin sensitivity, enhancing body sugar utilization and decreasing absorption of sugar from the intestines. Overall, we can summarily say that Metformin improves overall sugar metabolism (I have long supported reducing carbohydrate consumption as an adjunct in controlling cancer, perhaps to my colleagues’ consternation if not ridicule. Sugar and cancer is a very important theme, though usually under appreciated by conventional oncologists despite the strength of corollary data. But alas, the topic would be a whole separate blog)

Given so many modern illnesses (eg hyperlipidemia, obesity, diabetes etc) resulting from deranged carbohydrate metabolism, it is not hard to imagine that Metformin may have a role to play in the treatment of conditions resulting from defective insulin signalling (incl. polycystic ovary syndrome [PCOS], infertility, non-alcoholic fatty liver disease (NAFLD) or steato hepatitis, metabolic syndrome X, etc), and these could all be considered “off-label” uses for Metformin as a drug .

A higher incidence of cancer in patients with diabetes has been observed for a century, so much so that Dr Anna Barker, deputy director at the National Cancer Institute estimated that the obesity and diabetes pandemic will cause an additional 30-40% increase in incidence of total solid tumour cancers over the next 10 years – notably in breast, prostate, and colorectal cancer (Financial Times, Oct 1st, 2008). So it makes common sense that an anti-diabetic medicine may somehow inhibit cancer.  More recently, despite many mainstream oncologists curiously still denying a role of sugar and diet for cancer control, science has reviewed an emerging key role for insulin and sugar metabolism or insulin signalling in determining cancer risk, tumor growth or cancer progression (See recent review “Insulin, Insulin-like growth factors, Insulin resistance and neoplasia” by Pollack MN of McGill University in Am J Clin Nutri 2007 Sep;86(3):s820-2 for an overview), then it is no surprise that Metformin has off-label application potential in cancer treatment, as do drugs from another class of anti-diabetic agents, the PPAR agonists [discussion to be posted in this blog soon].

And there is a bit of evidence for this:-

a) In Vitro (cellular evidence):

Active against breast cancer (Zakikhani M, Cancer Res. 2006 Nov 1;66(21):10269-73), ovarian cancer (Gotlieb WH et al. Gynecol Oncol. 2008 Aug;110(2):246-50), prostate cancer (Ben Sahra I, et al. Oncogene. 2008 Jun 5;27(25):3576-86), glioma brain cancer (Isakovic A, Cell Mol Life Sci. 2007 May;64(10):1290-302).

Observed mechanisms of action of Metformin against various cancers seems mainly to be related to apoptosis and includes decrease in cyclin D1, AMPK activation leading to inhibition of mTOR and a reduction in translation initiation, selective toxicity to p53-deficient cells, and induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation.

b) In Vivo (animal evidence):

Prevention of pancreas cancer in hamsters (Schneider MB, Gastroenterology. 2001 Apr;120(5):1263-70)

Metformin inhibits development of breast cancer in mice (Anisimov VN, : Bull Exp Biol Med. 2005 Jun;139(6):721-3)

Metformin suppresses intestinal polyp growth in mice (Tomimoto et al. 2008)

Metformin attenuates growth of lung cancer in mice (Algire C. et al, Endocr Relat Cancer. 2008 Sep;15(3):833-9)

Metformin inhibits prostate cancer (Ben Sahra I, et al. Oncogene. 2008 Jun 5;27(25):3576-86)

c) Clinical (human evidence):

Dr. Dario Alessi’s research (U. of Dundee) involving data from patient records over ten years, have shown that patients on metformin showed anywhere between a 30-40% protection against all forms of cancer. While this and lowered instance of breast cancer in women with diabetes treated with Metformin has been known for a while, but recent work presented this year demonstrating Metformin’s role in increasing the response rates of breast cancer patients with diabetes is very exciting:

“Using the M. D. Anderson Breast Medical Oncology database, Drs. Gonzalez-Angulo, Jiralerspong and their team at MD Anderson identified 2,529 women with early-stage breast cancer who received chemotherapy. Of the patients, 68 were diabetic but not taking metaformin and 87 were diabetic and taking the drug. The researchers found that the pathologic complete response rates in the breast cancer patients taking Metformin was 24 percent, three times higher than the rates in patients not taking the drug”

When interviewed, Dr. Gonzalez-Angulo thinks that the result maybe from decreased insulin levels as insulin is a known potent growth factor for cancer.  The MD Anderson doctors are planning a trial of Metformin in metastatic breast cancer patients who are obese (and who may thus have insulin resistance and high circulating insulin levels).

My take

Such a benign drug as Metformin can be safely given as an off-label adjunctive treatment in cancer patients, especially breast, ovarian, colorectal, prostate, pancreas and perhaps in glioma patients who have Type 2 diabetes, exhibit metabolic syndrome X, who have elevated circulating insulin levels, or are obese, or even simply those who cannot or do not adhere to a low carb low fat diet.

Intriguingly, Metformin may also promote longevity (independent of cancer risks), but that will be the the topic of another blog!

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  1. N Valiunas
    October 22, 2009 at 5:58 pm

    In the recent studies, “small” does of metformin were found to delay relapse in breast cancer patients.

    What is your recommended dose of metformin, used off-label by a woman who has had surgery to remove the tumor and recently completed chemotherapy?

    i.e., in your opinion, what is the best dosage to administer?

    Thank you.

  2. October 22, 2009 at 6:28 pm

    Thankyou for your interest in my blog. Since I am unable to recommends specific dosages for individuals who are not actual patients of ours, I suggest that you refer to published dosages used in trial(s) and discuss what would be appropriate dose to apply in the specific patient concerned with the physician in charge of her care.

  3. Jag
    November 2, 2009 at 2:37 pm

    Dear Dr.Chang,
    May I know the dose of metformin that was used in the trials .Thanks.
    Jag

  4. November 2, 2009 at 4:22 pm

    The Metformin dose for adjuvant use in breast cancer ib an currently active trial NCT00909506 is 500 – 1000mg a day which is the usual dose for the drug in its use for diabetes.

  5. Jag
    November 2, 2009 at 5:10 pm

    Dear Dr.Chang,
    Thanks a lot for your kind reply.Does Metformin won’t cause hypoglycaemia in non diabetic cancer patients if it is administered to them?Is there any risk in non diabetic cancer patients if Metformin is used by them?Your take pls.
    Regards,
    Jag

  6. May 2, 2010 at 6:24 am

    I really enjoyed reading your blog. Kept my interest and was easy to understand. Good Job!

  7. September 9, 2010 at 12:52 am

    Dr Chang… My husband has terminal colorectal cancer mets to the lungs.The tumors are not growing , not shrinking so that is what we are thankful for now. Is there a possibility this Metforman could help him. His appetite is fantastic he has not lost weight and lives life to the fullest everyday. Would there be any interference with his Chemo? Thank you I will look forward to your reply. Thank you for your interest in research, with out people like you we would have lost him already.

    • November 1, 2010 at 2:06 am

      Although there is some very preliminary data that Metformin could be preventative of colon cancer, there is no evidence (human or animal) that it is useful as a treatment for colorectal cancer. There are many other agents that I have blogged or will eventually blog here that are more proven for colorectal than Metformin (e.g. tagament, PPAR agonists, statins, cox-2 inhibitors …) Good luck to your husband.

  8. Donna Fandrich
    October 31, 2010 at 2:04 am

    can metformin be used for someone already diagnosed with non-small cell lung cancer with lymph involvement. If so what would the benefits be?

    • November 1, 2010 at 2:03 am

      There is no date as of yet to show that metformin is clinically useful for non-small cell lung cancer. There are some interesting preliminary test-tube data and one animal study I believe, but that does not constitute adequate evidence to warrant its use.

  9. mcfarlane45@yahoo.com
    January 26, 2011 at 8:26 pm

    Dr.Chang, I was diagnosed with PC, small cell. I had metastasized to the bone by the time of diagnosis, 9/17/07. Are there trials/results relating to useful benefits of Metformin?

    • January 28, 2011 at 5:26 am

      Small cell prostate cancer is quite rare and obviously no clinical studies have been done with Metformin. Even with the usual prostate cancer, while there is some laboratory evidence of possible anti-cancer effect, there are no clinical studies as yet to say that it is an effective treatment. One study did show however that metformin use did not alter outcome of diabetic men with prostate (usual type, not small cell) cancer.

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