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Type: Artigo de periódico
Title: Metformin Amplifies Chemotherapy-induced Ampk Activation And Antitumoral Growth.
Author: Rocha, Guilherme Z
Dias, Marília M
Ropelle, Eduardo R
Osório-Costa, Felipe
Rossato, Franco A
Vercesi, Anibal E
Saad, Mario J A
Carvalheira, José B C
Abstract: 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.
Subject: Amp-activated Protein Kinases
Antineoplastic Agents
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cell Survival
Drug Synergism
Enzyme Activation
Hypoglycemic Agents
Mice, Scid
Signal Transduction
Tor Serine-threonine Kinases
Xenograft Model Antitumor Assays
Citation: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research. v. 17, n. 12, p. 3993-4005, 2011-Jun.
Rights: fechado
Identifier DOI: 10.1158/1078-0432.CCR-10-2243
Date Issue: 2011
Appears in Collections:Unicamp - Artigos e Outros Documentos

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