Potential applications for biguanides in oncology

Abstract

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

“…2A and Supplementary Figure S2). Although biguanide, the most widely used antidiabetic drug, is known to exert its anticancer effects through activation of AMPK and consequent inhibition of the mTOR pathway, 32,33 this AMPK-dependent mTOR inhibition was not observed in our experiment.…”

“…The use of other biguanides such as phenformin could be another way to decrease toxicity, as its CSF concentration is much higher than that of metformin. 32 In summary, the combination of 2DG and metformin was not cytotoxic toward GBM-TS but did effectively decrease the stemness and invasion capacity of GBM-TS, and showed potential survival benefits in a mouse orthotopic xenograft model. We believe that by targeting cells that give rise to TS, this dual inhibition of bioenergetic pathways could be helpful in the treatment of GBM patients.…”

“…Pollak also noted the possibility of short-term use of metformin at higher doses. 32 Because metformin alone at a dose of 500mg/kg failed to show anticancer effect in an in vivo setting, the dose of metformin required for anticancer effects when used in combination with 2DG needs to be confirmed. The use of other biguanides such as phenformin could be another way to decrease toxicity, as its CSF concentration is much higher than that of metformin.…”

Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation

“…Furthermore, many drugs in clinical use for other diseases (e.g., diabetes, various inflammatory conditions, heart disease) have anticancer effects in vitro (8) and, hence, have the potential to be repurposed for treating cancer patients. For example, epidemiological data and preclinical experiments suggest the use of diabetes drug metformin for cancer prevention and treatment in nondiabetics (14)(15)(16), and clinical trials are in progress. For these reasons, we have initiated a phenotypic approach to personalized medicine in which patient-derived tumor cells will be screened for their response to a variety of FDAapproved drugs.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] While it might appear intuitive that deregulated cancer metabolism can activate pro-survival signaling and decrease druginduced apoptosis to provide a general, unspecific protection against cell injuries induced by multiple types of cytotoxicities, it is worth noting that resistance to oncogene-mediated targeted therapy has been shown to require a shift toward the very same metabolic state that is controlled by growth factor signaling. 20,21 In cancer cells sensitive to lapatinib, the small-molecule dual inhibitor of the oncogenes EGFR and HER2, receptor tyrosine kinase signaling is disrupted, and activity of its Ras, PI3K, and mTOR downstream effectors is abrogated; because oncogenedependent metabolic rewiring is prevented, cancer cell death is observed.…”