A newly synthesized bifunctional inhibitor, W-77, enhances adriamycin activity against human ovarian carcinoma cells.

Abstract

A newly synthesized calmodulin antagonist, (S)-P-(2-aminoethyloxy)-N-[2-(4-benzyloxy-carbonylpiperazinyl++ +)-1-(P-methoxybenzyl)ethyl]-N-methylbenzenesulfonamide dihydrochloride (W-77), acts as a calcium-independent uncompetitive antagonist which binds to glutathione-S-transferase (GST). We purified GST from human placenta using drug affinity chromatography on a column of W-77 coupled with Sepharose 6B and demonstrated that W-77 bound to GST. A spectrophotometric assay also showed that W-77 inhibited GST activity. We prepared Adriamycin-resistant and -sensitive cells from human ovarian serous cystadenocarcinomas. Immunoblot analysis revealed that GST expression was increased in the Adriamycin-resistant cells. We also purified GST from Adriamycin-resistant cells and found that W-77 bound to the GST obtained from these ovarian carcinoma cells. Adriamycin resistance was partially overcome by the addition of W-77 (10 microM) to the cultured cells. In addition, we investigated the effect of W-77 on P-glycoprotein. Northern blot analysis revealed MDR1 gene expression in Adriamycin-resistant cells. Although W-77 was less potent in increasing the intracellular Adriamycin content than verapamil, it was more effective in overcoming Adriamycin resistance. These results suggest that W-77 enhances the antitumor activity of Adriamycin by inhibiting both GST and P-glycoprotein.

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@article{Maeda1993ANS, title={A newly synthesized bifunctional inhibitor, W-77, enhances adriamycin activity against human ovarian carcinoma cells.}, author={Osamu Maeda and Motomu Terasawa and Takashi Ishikawa and Hidenori Oguchi and Kyosuke Mizuno and Mikio Kawai and Fumitaka Kikkawa and Y Tumoda and Hidemasa Hidaka}, journal={Cancer research}, year={1993}, volume={53 9}, pages={2051-6} }