INDUCTION OF APOPTOSIS BY FENRETINIDE (4HPR) IN HUMAN OVARIAN-CARCINOMA CELLS AND ITS ASSOCIATION WITH RETINOIC ACID RECEPTOR EXPRESSION

We previously reported that fenretinide (4HPR) is effective against a human ovarian carcinoma xenografted in nude mice. The effects of 4HPR on ovarian tumors have been further studied in in vitro ovarian carcin oma cell lines A2780, IGROV-1, SW626 and OVCA432. A2780 was the most s ensitive line: 50% growth inhibition was obtained after 3 days of expo sure to 1 mu M 4HPR, a pharmacologically achievable concentration, whe reas approx. 10 mu M 4HPR gave a similar inhibition in the other cell lines. All-trans retinoic acid (RA), at doses up to 10 mu M, did not i nhibit cell proliferation. Gel electrophoresis of DNA from either deta ched or attached A2780 cells treated with 4HPR revealed DNA ladders in detached cells. Apoptosis was also evidenced in detached 4HPR-treated cells by flow cytometry and microscopic observation. The difference i n cell line sensitivity to the anti-proliferative effect of 4HPR was n ot related to drug uptake or efflux. Only A2780 cells, the most sensit ive to 4HPR, expressed constitutive levels of RAR beta; moreover, the levels of RAR alpha and RAR gamma expression in these cells were highe r than in the other cell lines. In A2780 cells, the association of an IC20 of 4HPR to cisplatin resulted in a strong potentiation of the ant i-proliferative effect. These data show (i) that 4HPR, in contrast to RA, has an anti-proliferative effect in human ovarian carcinoma cells which is related to induction of apoptosis and (ii) that among the tes ted lines, the most responsive to the drug expressed RAR beta and the highest levels of RAR alpha and RAR gamma. The results also suggest th at 4HPR can potentiate the effects of cisplatin in ovarian carcinoma. (C) 1996 Wiley-Liss, Inc.