Roles of the Bcl-2/Bax ratio, caspase-8 and 9 in resistance of breast cancer cells to paclitaxel.
The goal of this study was to establish paclitaxel resistant MCF-7 cells, as in vitro model, to identify the molecular mechanisms leading to acquired chemoresistance in breast cancer cells. Resistant cells were developed by stepwise increasing exposure to paclitaxel. Gene expression levels of Bax and Bcl-2 along with protein levels of 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 fluorescence activated cell sorting (FACS). As an important indicator of resistance to chemotheraputic agents, the Bcl-2/Bax ratio showed a significant increase in both MCF-7/Pac5nM and MCF-7/Pac 64nM cells (p<0.001), while caspase-9 levels 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 the idea that paclitaxel induces apoptosis in a mitochondrial-dependent manner. Identifying breast cancer patients with a higher Bcl-2/Bax ratio and caspase 9 level and then inhibiting the activity of these proteins may improve the efficacy of chemotheraputic agents.
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran E-mail : drnsamadi@yahoo.com.
Simin
S
Sharifi
Jaleh
J
Barar
Mohammad Saeid
MS
Hejazi
Nasser
N
Samadi
D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; D053453:Caspase 9; D017239:Paclitaxel