Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

Abstract

Purpose: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.Experimental Design: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.Results: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G 2 -M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.Conclusion: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. Clin Cancer Res; 17(12); 3993-4005. Ó2011 AACR.

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

“…Metformin may inhibit IkB and IKKa/b subunits and hence NF-kB and may prevent the translocation of NF-kB from the cytoplasm to the nucleus (31). Metformin seems to downregulate genes involved in mitosis and may act synergistically in this setting with taxanes (32). Metformin may also act via the DNA damage response mechanisms through ataxia telangiectasia mutated (ATM) and Chk2 (33), also potentially accounting for the cancer prevention effect.…”

Antiproliferative action of metformin in human lung cancer cell lines

“…Mazzone et al reported that diabetes patients with lung cancer who were previously treated with metformin or thiazolidinediones had a lower incidence of metastatic disease at the time of diagnosis and a reduced risk of death compared to those who did not receive the same treatment (4). Thereafter, the antiproliferative action of metformin was confirmed via in vivo and in vitro experiments in various cancer cell lines including breast (5)(6)(7)(8), prostate (9), pancreas (10), and ovarian cancer (11)(12)(13) as well as lung adenocarcinoma (8).…”

“…Despite these findings, the precise mechanisms of the metformin-induced effects are not fully understood. In particular, controversy remains about whether metformin is apoptotic (6,10) or just cytostatic (5,9) and whether it kills cancer cells synergistically with cytotoxic agents including cisplatin (11,13), paclitaxel (8), and doxorubicin (17), or if it is antagonistic to cisplatin (18,19).…”

Immune-mediated antitumor effect by type 2 diabetes drug, metformin

“…Combined use of metformin with chemotherapeutic agents such as cisplatin has also yielded clinical benefits (25,26). Regarding the anticancer mechanism, metformin appears to preferentially kill cancer-initiating/stem cells from glioblastoma (27), breast (28) and ovarian cancers (29) via AMPactivated protein kinase (AMPK) activation.…”