Roles of the Bcl-2/Bax Ratio, Caspase-8 and 9 in Resistance of Breast Cancer Cells to Paclitaxel

Abstract

The goal of this study was to establish paclitaxel resistant MCF-7 cells, as in vitro model, to identify themolecular mechanisms leading to acquired chemoresistance in breast cancer cells. Resistant cells were developedby stepwise increasing exposure to paclitaxel. Gene expression levels of Bax and Bcl-2 along with protein levelsof caspase-8 and caspase-9 were evaluated in two resistant cell lines (MCF -7/Pac64 and MCF -7/Pac5 nM).Morphological modifications in paclitaxel resistance cells were examined by light microscopy and fluorescenceactivated cell sorting (FACS). As an important indicator of resistance to chemotheraputic agents, the Bcl-2/Baxratio showed a significant increase in both MCF-7/Pac5nM and MCF-7/Pac 64nM cells (p<0.001), while caspase-9levels were decreased (p<0.001) and caspase-8 was increased (p<0.001). FACS analysis demonstrated that MCF-7/Pac64 cells were smaller than MCF-7 cells with no difference in their granularity. Our results support theidea that paclitaxel induces apoptosis in a mitochondrial-dependent manner. Identifying breast cancer patientswith a higher Bcl-2/Bax ratio and caspase 9 level and then inhibiting the activity of these proteins may improvethe efficacy of chemotheraputic agents.