ALL-TRANS, 13-CIS AND 9-CIS RETINOIC ACIDS INDUCE A FULLY REVERSIBLE GROWTH-INHIBITION IN HNSCC CELL-LINES - IMPLICATIONS FOR IN-VIVO RETINOIC ACID USE

Retinoids are a group of vitamin A analogues that have shown promise a s chemopreventive and therapeutic agents in many types of malignancy a nd have been entered in clinical trials with some successful results. To better understand the mechanism that mediates retinoid action and t he antiproliferative effects, we treated 7 human oral squamous-cell ca rcinoma (SCC) cell lines (FADU, HEp-2, CCL-17, SCC-9, SCC-15, SCC-25 a nd HN-212) with in 10(-6) M of all-trans retinoic acid (ATRA), 9-cis a nd 13-cis retinoic acid (RA) in continuous for different periods of ti me. We assessed the extent of growth inhibition, the stability of the anti-proliferative effect and the mRNA expression levels (by RT-PCR) o f RA receptors (RARs), retinoid X receptors alpha (RXR alpha) and cyto solic RA-binding proteins (CRBP I and CRABP II) in treated cells compa red with controls. The data obtained showed that all 3 RAs were able t o inhibit the cellular growth of the tested cell lines, although to a different extent. The cis compounds were able to inhibit the prolifera tion of all cell lines, whereas ATRA was ineffective in inhibiting the proliferation of the CCL-17 cell line, which was naturally resistant to ATRA concentrations in the range between 10(-5) and 10(-6) M. All i nhibitory effects were completely reversible since all cell lines rest ored their normal growth proliferation within few days after drug remo val. RT-PCR analysis of the receptor and cell binding protein status o f control and treated cells showed a good correlation between growth i nhibition and induction of, or increase in, the expression levels of R AR beta in RA-treated cells. No differences were observed in RAR alpha and RXR alpha mRNA expression levels between control and treated cell s. CRBP I, CRABP II and RAR gamma mRNA levels increased in some treate d cell lines but not in all. (C) 1997 Wiley-Liss, Inc.