INHIBITION OF PROLIFERATION AND INDUCTION OF APOPTOSIS IN CERVICAL-CARCINOMA CELLS BY RETINOIDS - IMPLICATIONS FOR CHEMOPREVENTION

The effects of retinoids including all-trans-retinoic acid (ATRA), 13- cis-retinoic acid (13CRA), and N-(4-hydroxyphenyl)retinamide (4-HPR) o n several cervical carcinoma cell Lines in culture were investigated a s a prelude to investigating the mechanisms underlying the chemopreven tive potential of retinoids in cervical cancer. We found that when use d at a concentration of 1 mu M, 13CRA and ATRA inhibited the prolifera tion of three cell lines (ME-180 [HPV 68], SiHa [HPV 18], and HT-3 [HP V-]) by about 80% after a seven-day treatment. Three other cell lines (MS-751 [HPV 18], HeLa [HPV 18], C-33A [HPV-]) were moderately inhibit ed (30-48%), and two (C-4 II [HPV 18], CaSki [HPV 16]) responded poorl y (< 25% inhibition). 4-HPR failed to inhibit the growth of any of the se cell lines when used at 1 mu M; however, when used at 5 or 10 mu M, it induced apoptosis as evidenced by DNA fragmentation in several of the cell lines and was more potent in this effect than 10 mu M ATRA. R etinoids that induce apoptosis in malignant cells may be able to exert similar effects on premalignant cells. Such retinoids would be expect ed to exhibit greater potency as chemopreventive agents than retinoids that exert only cytostatic effects. (C) 1995 Wiley-Liss, Inc.