Already the most widely used antidiabetes drug in the world, metformin is emerging as a promising, targeted, and intensely studied cancer prevention drug as well. It is off-patent, inexpensive, and has an extensive safety record. Epidemiologic and experimental data suggest cancer preventive activity. At the molecular level, metformin activates AMPK (a kinase regulated by the tumor suppressor gene LKB1), which inhibits mTOR.
This issue of the journal features four primary preclinical research articles (1–4) and two perspectives (5, 6) that add substantially to the published body of work on metformin for cancer prevention, including several primary (7–11) and other (12–14) metformin articles that have appeared in recent past issues of the journal. In this issue, Algire and colleagues (1) report their discovery of a novel mechanism of metformin activity in attenuating endogenous (peraquat or Ras induced) reactive oxygen species and DNA damage and mutations; metformin has no direct hydroxy radical scavenging effect. Two of the present articles report novel mechanisms relevant to hepatocellular cancer. Bhalla and colleagues (2) report that metformin prevented liver carcinogenesis and did so through inhibiting pathways driving hepatic lipogenesis; ectopic expression of the lipogenic transcription factor SREBP1c rescued metformin-mediated growth inhibition. Subramaniam and colleagues (3) studied the effects of metformin (and another small-molecule AMPK activator) on Bambi expression in hepatic stellate cells (HSC), which play an important role in the hepatocellular cancer precursors liver injury, inflammation, and fibrosis. They found that metformin increased Bambi expression (by stabilizing Bambi mRNA), which induced Wnt/β-catenin signaling in quiescent (but not in activated) HSCs, as shown mechanistically via targeted abrogation of Bambi or its ectopic expression. Vitale-Cross and colleagues (4) report that metformin prevented cancer in an oral-specific carcinogenesis model via inhibiting TORC1 in the basal epithelial layer of dysplastic oral lesions.
All of these studies represent fascinating science on an old drug that may be repositioned, or that could be a lead compound for analog development, for cancer prevention. The opportunities are exciting, but gaps in our knowledge of metformin remain to be filled before we can optimize the design of personalized clinical trials in selected populations.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.