ALL-TRANS-RETINOIC ACID ENHANCES CISPLATIN-INDUCED APOPTOSIS IN HUMANOVARIAN ADENOCARCINOMA AND IN SQUAMOUS HEAD AND NECK-CANCER CELLS

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, al l-trans retinoic acid (ATRA) causes apoptosis in certain cells. We stu died the interaction of cisplatin and ATRA in human ovarian adenocarci noma cells 2008, in human head and neck squamous carcinoma cells UMSCC 10b, and in their respective cisplatin-resistant sublines. ATRA enhanc ed the cytotoxicity of cisplatin. The interaction of the drugs was syn ergistic in combination index-isobologram analyses (combination index <0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhib ited the cellular accumulation of the cisplatin analogue [H-3]cis-dich loroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The ap optotic mechanism of cell death was confirmed by demonstrating cleavag e of poly(ADP-ribose)polymerase and by morphological analysis. The com bined treatment with ATRA and cisplatin induced apoptosis in significa ntly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian an d head and neck carcinoma cells.