METFORMIN AMPLIFIES CHEMOTHERAPY-INDUCED AMPK ACTIVATION AND ANTITUMORAL GROWTH.

Source

Internal Medicine, UNICAMP.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

Human tumors were xenografted into SCID mice and the cancer cell lines were treated with only 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.

RESULTS:

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 the tumor growth and increased apoptosis in tumor-bearing mice, when compared to individual drug treatments.

CONCLUSIONS:

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.

Advertisements