Repurposing metformin for cancer treatment: current clinical studies

Abstract

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression

“…Hence, methionine restriction metabolically primes breast cancer cells to targeted agents that activate cell death by exposing a targetable vulnerability, namely enhanced cell surface expression of TRAIL-R2. Intriguingly, the diabetes medication metformin mimics many of the effects of methionine restriction, including disruption of methionine metabolism via inhibition of the functionally linked folate cycle in the one-carbon metabolic pathway, inhibition of the mechanistic target of rapamycin (mTOR), broad antitumor activity, improved insulin sensitivity, and prolonged lifespan [15][16][17][18][19].…”

“…Metformin use has been associated with reduced incidence of a broad range of tumor types and reduced cancer mortality in many epidemiologic studies [19][20][21][22]. However, the antitumor mechanisms of metformin are not well understood.…”

Metformin: Hype or Hope for Cancer

“…There are 3 clinical studies currently evaluating survival benefit of metformin in breast cancer but the results are not obtained yet. 59 The long-term results of these studies may clear up the utility of metformin in cancer treatment.…”

“…It was reported to inhibit apoptosis of CD8+ tumor infiltrating lymphocytes and CD8+ tumor induced lymphocytes and increases CD8+ memory T cells. 58,59 Some studies suggested that metformin may sensitize cancer cells to some chemotherapy agents, including cisplatin, doxorubicin and paclitaxel. 34,55,60 Metformin was also found to increase radiosensitivity of cancer cells through ATM and AMPK.…”

Metformin: clinical topics and new mechanisms of action

“…Eligible trials also showed no significant effect of metformin on all-cause mortality [28]. Nevertheless, metformin has been tried with some success in clinical chemotherapy trials for treatment of various types of cancer, and many trials are ongoing, including for breast, prostate, colorectal, pancreas, and lung cancers [29].…”