Abstract: Apoptotic resistance is the main obstacle for treating cancer patients with chemotherapeutic drugs. Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-KD ATP-dependent drug efflux protein. Functional P-gp can confer resistance to activate caspase-8 and -3 dependent apoptosis induced by a range of different stimuli, including tumor necrosis and chemotherapeutic drugs such as docetaxel and vincristine. We demonstrated here that comparison of sensitive KB cells, P-gp positive (P-gp+ve) KBv200 cells were extremely resistant to apoptosis induced by docetaxel. FG020326, a pharmacological inhibitor of P-gp function, could enhance concentration-dependently the effect of docetaxel on cell apoptosis and sensitize caspase-8, -9 and -3 activation in P-gp overexpressing KBv200 cells, but not in KB cells. Therefore, the enhancement of caspase-8, -9 and -3 activation induced by docetaxel may be one of the key mechanisms of the reversal of P-gp mediated docetaxel resistance by FG020326.
Keywords: cancer; multiple drug resistance; FG020326; P-glycoprotein; apoptosis; caspase
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Wang, X.-W.; Wang, X.-K.; Zhang, X.; Liang, Y.-J.; Shi, Z.; Chen, L.-M.; Fu, L.-W. FG020326 Sensitized Multidrug Resistant Cancer Cells to Docetaxel-Mediated Apoptosis via Enhancement of Caspases Activation. Molecules 2012, 17, 5442-5458.
Wang X-W, Wang X-K, Zhang X, Liang Y-J, Shi Z, Chen L-M, Fu L-W. FG020326 Sensitized Multidrug Resistant Cancer Cells to Docetaxel-Mediated Apoptosis via Enhancement of Caspases Activation. Molecules. 2012; 17(5):5442-5458.
Wang, Xiu-Wen; Wang, Xiao-Kun; Zhang, Xu; Liang, Yong-Ju; Shi, Zhi; Chen, Li-Ming; Fu, Li-Wu. 2012. "FG020326 Sensitized Multidrug Resistant Cancer Cells to Docetaxel-Mediated Apoptosis via Enhancement of Caspases Activation." Molecules 17, no. 5: 5442-5458.