Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

• Published in: Clinical cancer research 2011-06, Vol.17 (12), p.3993-4005
• Main Authors: ROCHA, Guilherme Z, DIAS, Marília M, ROPELLE, Eduardo R, OSORIO-COSTA, Felipe, ROSSATO, Franco A, VERCESI, Anibal E, SAAD, Mario J. A, CARVALHEIRA, José B. C
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Antimetabolites - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Deoxyglucose - pharmacology; Drug Synergism; Enzyme Activation - drug effects; Humans; Hypoglycemic Agents - pharmacology; Male; Medical sciences; Metformin - pharmacology; Mice; Mice, SCID; Neoplasms - metabolism; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2243

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. 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. 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. 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.