A NEWLY SYNTHESIZED BIFUNCTIONAL INHIBITOR, CKA1083, ENHANCES ADRIAMYCIN ACTIVITY AGAINST HUMAN OVARIAN-CARCINOMA CELLS

Background - A newly synthesized drug, CKA1083 benzyloxy-carbonylpiper azinyl)-1-(P-methoxybenzyl) ethyl]-N-methyl-N(5-isoquinolinesulfonamid e)), has the same glutathione-S-transferase (GST)-binding site structu re as W-77, a bifunctional inhibitor that enhances the cytotoxicity of Adriamycin for human ovarian carcinoma cells. We examined the effects of CKA1083 on the cytotoxicity of Adriamycin and the resistance of hu man ovarian carcinoma cells to this drug. Materials and Methods - We u sed GST-pi transfected cells and Adriamycin-sensitive or -resistant ce lls of human ovarian carcinoma. GST-pi activity the intracellular Adri amycin content, and the cytotoxicity of Adriamycin in these cell lines in the presence or absence of CKA1083 were measured and compared to t he findings obtained with W-77 or verapamil. Results - CKA1083 inhibit ed GST-pi activity in an uncompetitive manner and more strongly than W -77. It enhanced the cytotoxicity of Adriamycin for GST-pi transfected cells by about 3-times. Further; CK41083 increased the intracellular Adriamycin content about 3-fold in two Adriamycin-resistant cell lines (NOS2AR and NOS3AR). CKA1083 (10 mu M) reduced the IC50 of Adriamycin to 1/38 in NOS2AR cells and 1/21 in NOS3AR cells, and overcame Adriam ycin resistance more effectively than both W-77 and verapamil. Conclus ions CKA1083 enhanced the antitumor effect of Adriamycin more than W-7 7 by inhibiting both GST activity and P-glycoprotein.