Paclitaxel effect on the IRS/PI3-kinase/Akt/mTOR pathway in breast cancer adenocarcinoma and lung cancer carcinoma

Author(s)

Guilherme Zweig Rocha

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2010-08-27

Examining board members

José Barreto Campello Carvalheira; José Andrés Yunes; Miriam Galvonas Jasiulionis

• Advisor: José Barreto Campello Carvalheira

Abstract

Metformin is a widely-used antidiabetic drug whose anti-cancer effects, mediated by the activation of 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 SCID mice and the cancer cell lines were treated only with paclitaxel or 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, demonstrate 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 G2/M phase of the cell cycle, decreased tumor growth and increased apoptosis in tumor-bearing mice, when compared to individual drug treatments. We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism illustrates how different drugs may cooperate to augment anti-growth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment (AU)

• FAPESP's process: 07/06221-8 - Paclitaxel effect on the IRS/PI3-kinase/Akt/mTOR pathway in breast cancer adenocarcinoma cell line
• Grantee: Guilherme Zweig Rocha
• Support Opportunities: Scholarships in Brazil - Master