PSC 833 modulation of multidrug resistance to paclitaxel in cultured human ovarian carcinoma cells leads to apoptosis.

BACKGROUND: Multidrug resistance (MDR) modulator PSC 833 has been shown to modulate multidrug resistance in Pg-p-positive human ovarian carcinoma cells A2780/ADR. Co-treatment of A2780/ADR cells with paclitaxel (PTX) and PSC 833 resulted in the restoration of PTX-sensitivity comparable to that in parental A2780 cells. RESULTS: The flow cytometry experiments presented here showed PTX-(A2780) and PTX plus PSC 833 (A2780/ADR)-induced cell accumulation in the G2/M-phase of the cell cycle with concomitant appearance of apoptotic cells with sub-G0 (hypodiploid) DNA content. Furthermore, these events were accompanied by the appearance of poly(ADP-ribose) polymerase (PARP) cleavage, up-regulation of Bax, p53 and p21WAF1/CIP1 proteins and internucleosomal DNA fragmentation. Interestingly, we did not detect any significant alterations in Bcl-xL, CD95/Fas and Fas-L protein levels. CONCLUSION: These results demonstrate the PSC 833 reduced the Pg-p-mediated multidrug resistance in human ovarian carcinoma cells to PTX-induced apoptosis in vitro.