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  • Title: [Enhancement of FG020326 on sensitivity of MCF-7/ADR cells to taxotere via enhancing activation of caspase-8 and caspase-3].
    Author: Wang XW, Ding Y, Liang YJ, Chen LM, Shi Z, Yang XP, Gu LQ, Fu LW.
    Journal: Ai Zheng; 2004 Nov; 23(11 Suppl):1379-85. PubMed ID: 15566641.
    Abstract:
    BACKGROUND & OBJECTIVE: Multidrug resistance (MDR) is often characterized by over-expression of P-glycoprotein (P-gp) as drug efflux protein. Recent researches showed P-gp can inhibit caspase-dependent apoptosis, and protect MDR cells from apoptosis. This study was designed to investigate reversal effect of FG020326, a potent MDR modulator,on drug-resistance of MCF-7/ADR cells towards taxotere,and its mechanism. METHODS: Drug-resistant MCF-7/ADR cells, over-expressed P-gp, were cultured with FG020326 and taxotere. The reversal effect of FG020326 was assayed by MTT method. Apoptotic morphology of MCF-7/ADR cells was observed under fluorescent microscope after Hoechst33258 staining, cell apoptosis was measured by flow cytometry (FCM). Activation of caspase-8 and caspase-3 was measured by Western blot and colorimetric assay. RESULTS: FG020326 enhanced sensitivity of MCF-7/ADR cells to taxotere, and gave a 24-fold reversal of apoptosis-resistance with concentration of 10 micromol/L. Under effect of 10 micromol/L FG020326,chromatin condensation, apoptotic bodies, and sub-G1 peak were observed in MCF-7/ADR cells. Sensitivities of caspase-8 and caspase-3 were enhanced by demostrating cleavage of caspase-8, caspase-3,and PARP in MCF-7/ADR cells. Activities of caspase-3 and caspase-8 in MCF-7/ADR cells cultured with 10 micromol/L FG020326 and 0.1 micromol/L taxotere were increased in a time-dependent manner,and reached peak values at 48 h, which were significantly higher than those in cells cultured with taxotere alone. CONCLUSION: FG020326 may reverse drug-resistance of MCF-7/ADR cells towards taxotere through enhancing activation of caspase-8 and caspase-3 induced by taxotere.
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