DIFFERENTIAL-EFFECTS OF SYNTHETIC NUCLEAR RETINOID RECEPTOR-SELECTIVERETINOIDS ON THE GROWTH OF HUMAN NONSMALL CELL LUNG-CARCINOMA CELLS

Retinoids are promising agents for cancer chemoprevention and therapy. Nuclear retinoic acid receptors (RARs; RAR alpha, -beta, and -gamma) and retinoid X receptors (RXRs; RXR alpha, -beta, and -gamma) are thou ght to mediate most of retinoids' effects on cell growth and different iation. Because the majority of human non-small cell lung carcinoma (N SCLC) cell lines are resistant to all-trans-retinoic acid, we searched for more potent retinoids. Therefore, we examined the effects of 37 n atural and synthetic retinoids that exhibit specific binding to and tr ansactivation of individual RARs or RXRs on the proliferation of eight human NSCLC cell lines. All of these cells expressed mRNAs of the thr ee RXRs; however, they expressed varying levels of RAR alpha and RAR g amma, and only three of the eight cell lines expressed RAR beta mRNA. Cellular retinoic acid-binding proteins (CRABPs) I and II were detecte d in one and three of the eight cell lines, respectively. Only 8 of th e 37 retinoids exhibited growth-inhibitory activity (IC50, <10 mu M) a gainst at least two of the eight NSCLC cell lines. The active retinoid s included one (TD550) of five RAR alpha-selective, one (Ch55) of thre e RAR beta-selective, three (CD437, CD2325, and SR11364) of six RAR ga mma-selective, and one (CD271) of four RAR beta/gamma-selective retino ids. The potency of these retinoids was low (IC50, >1 mu M), except fo r CD437, which was very potent (IC50, 0.1-0.5 mu M). The six RXR-selec tive retinoids were mostly inactive even at 10 mu M. However, combinat ions of RAR-selective and RXR-selective retinoids exhibited additive e ffects. There appeared to be no simple correlation among the histologi cal type of the NSCLC (adeno-or squamous), the levels of nuclear recep tors or CRABPs, and the response of the cells to the growth-inhibitory effects of retinoids. Nevertheless, in contrast with former studies w ith natural retinoids, these results suggest that several synthetic re tinoids do exhibit inhibitory activity against NSCLC cells, and some o f them may be useful clinically.