Worldwide, metformin is the most commonly prescribed drug for type 2 diabetes. It is also used to treat gestational diabetes and metabolic syndrome, and preclinical in vitro and animal studies have also linked metformin to reduced levels of inflammatory markers and inhibition of tumor growth.1-2

Since 2005, clinical reports have accumulated suggesting that patients with diabetes who take metformin also experience lower cancer rates.3 Over the past 2 years, metformin has been found in retrospective studies to be associated with improved ovarian and pancreatic cancer survival rates, and to have a promising potential role in prostate cancer treatment, among others.4

RELATED: Study Backs Benefits of Metformin in Prostate Cancer

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But exactly why patients taking metformin for diabetes should face better cancer risks has been far from clear. Now, efforts to better understand the molecular underpinnings of the antidiabetes benefits of metformin seem to point to modes of action that could plausibly impact tumor growth.1

Metformin inhibits hyperinsulinemia, which has been tied to tumorigenesis.1

Research shows that metformin also appears to target mitochondrial electron transport, decreasing adenosine triphosphate (ATP) production, suggesting a plausible direct mechanism of action for anticancer activity.1 Mitochondria are membrane-bound organelles found within cellular nuclei that carry their own genomes separate from that of their host cells. Frequently described as cellular “power plants”, they produce cellular ATP, a source of chemical energy.

Metformin’s targeting of mitochondrial function appears to involve two separate mechanisms or pathways: decreased glucagon-induced cyclic adenosine monophosphate (cAMP) synthesis and activation of 5′ adenosine monophosphate–activated protein kinase (AMPK).4

In addition, metformin might reduce mutagenesis and activate DNA repair mechanisms including tumor-suppressor protein.1

“Through inhibition of mitochondrial complex I, metformin reduces production of reactive oxygen species, oxidative stress and DNA damage, therefore reducing the risk of mutagenesis,” reported the authors of a recent review article published in Nature Reviews Endocrinology.1 “…Metformin, as a cellular stressor, activates reparatory processes, even in the absence of DNA damage, which might be protective against premalignant to malignant transformation.”

Separate preclinical research using another biguanide, phenformin, appears to confirm that mitochondrial DNA mutations affecting glucose import underlie biguanides’ inhibition of tumor growth, according to research published online in Nature in March 2014.5 Biguanides kill tumor cells through their effects on mitochondria, concluded the authors.5

Another recent preclinical study of both breast cancer cell lines and cancer stem cells bolsters the case that metformin activates AMPK to suppress mammalian target of rapamycin (mTOR), which is important in cell protein synthesis and survival.2 Hyperthermia potentiates this effect, inactivating mTOR, study authors reported.2  

“Metformin killed cancer cells and suppressed the proliferation of cancer cells,” they reported.2 “Importantly, the cytotoxicity of metformin alone or in combination with hyperthermia was significantly greater to CSCs [cancer stem cells] than to non-CSCs. The major molecular target of metformin alone or in combination with hyperthermia appeared to be AMPK/mTOR pathway.”

Given metformin’s relative safety and low cost, the authors suggested that it might prove to be a useful adjuvant to radiation oncology or chemotherapy.2

Time will tell; an April 2014 search of ClinicalTrials.gov identified 197 clinical trials already underway that are related to metformin and cancer.

References

  1. Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endrocrinol. 2014;10(3):143-156.
  2. 2. Lee H, Park HJ, Park CS, et al. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined. PLOS One. 2014;9(2):e87979.
  3. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304-1305.
  4. Ko EM, Walter P, Jackson A, et al. Metformin is associated with improved survival in endometrial cancer. Gynecologic Oncol. 2014;132(2):438-442.
  5. Birsoy K, Rossemato R, Lorbeer FK, et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014;508(7494):108-112.

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General Oncology