Metformin in ovarian cancer therapy: A discussion

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Preclinical Studies of Metformin and Ovarian Cancer

Metformin's indirect effect on ovarian cancer

Several preclinical studies demonstrate the metformin's indirect effect on OVC, the mechanism of which includes the inhibition of hepatic gluconeogenesis and increasing peripheral glucose uptake,^{[45],[46],[47]} subsequently resulting in lower glucose, insulin, and IGF-1 levels in circulation.^[48],[49] Hyperglycemia attenuates metformin sensitivity in OVC while stimulating the OVC progression.^[50],[51] Similarly, in hyperinsulinemia, IGF-1 levels also stimulate the risk of OVC by activating PI3K/Akt/mTOR pathway, through IGF-1R signaling.^{[37],[52],[53],[54]} A careful observation of the above data also suggested that the metformin cannot play an indirect effect in nondiabetic patients.^[55]

Conclusion
The epidemiologic and preclinical data evaluated in this review are supportive of the use of metformin for the prevention and treatment of OVC. Preclinical evidence suggests that metformin possesses anticancer effects on OVC. Results of clinical studies, although a few, suggest that using metformin, pertaining to its cumulative dose and duration of therapy, is associated with a decreased incidence of OVC in diabetic population. In addition, it is also found to be associated with a better survival of OVC patients with diabetes. There are many unanswered questions though, including: (1) Whether metformin has anti-cancer activity in nondiabetics? (2) Whether we can use tumor genetic profiling to identify patients who are most likely to benefit from metformin treatment? (3) Considering the supra-clinical doses of metformin used in preclinical in vitro models to obtain an antineoplastic effect, should the optimal dose of metformin for OVC be revised and/or should it need a new route of drug delivery? (4) Do the serious side effects of supra-clinical doses or long-term therapy of metformin exist? If so, how to avoid these side effects? Future studies are hoped to warrant such questions, the results of which should be of value in determining metformin as a standard line of treatment for OVC patients.