FG020326 sensitized multidrug resistant cancer cells to docetaxel-mediated apoptosis via enhancement of caspases activation.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Xiu-Wen WangLi-Wu Fu

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.

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Citations

Oct 19, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jian-Ye ZhangHu-Biao Chen

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Methods Mentioned

BETA
flow cytometry
fluorescence microscopy
Assay

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