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.


CONCLUSIONS
These results demonstrate the PSC 833 reduced the Pg-p-mediated multidrug resistance in human ovarian carcinoma cells to PTX-induced apoptosis in vitro.
Duraj
Jozef
J
Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava, Slovakia. exondura@savba.sk
Sedlak
Jan
J
Bies
Juraj
J
Chovancova
Jana
J
Chorvath
Branko
B
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003524:Cyclosporins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D017239:Paclitaxel; C070272:valspodar