INDUCTION OF APOPTOSIS IN HUMAN NONSMALL CELL LUNG-CARCINOMA CELLS BYTHE NOVEL SYNTHETIC RETINOID CD437

Retinoids are promising agents for the prevention and treatment of sev eral human malignancies including lung cancer. However, many lung canc er cell lines are resistant to the growth inhibitory effects of all-tr ans-retinoic acid (ATRA). Recently, we found that a new synthetic reti noid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic aci d (CD437), which binds selectively to nuclear RA receptor gamma, was t he most effective inhibitor of the growth of human non-small cell lung carcinoma (NSCLC) cells among 37 retinoids tested. After a 4-day trea tment with CD437 the growth of 8 NSCLC cell lines was inhibited with a n IC50 ranging from 0.13 to 0.53 mu M. In contrast, ATRA failed to inh ibit the growth of any of these cell lines by more than 43% after a 7- day treatment even at 10 mu M. The presence of detached rounded cells in treated cultures indicated that CD437 may induce apoptosis. Indeed, this was confirmed by the presence of 20-57% cells with a sub-G1 DNA content and by an enzyme-linked immunosorbent assay (ELISA) of apoptos is. Two retinoids, CD2366 and CD2665, which are antagonists of nuclear retinoid receptor activation, failed to inhibit the effect of CD437 o n the growth of the NSCLC cell lines. CD437 failed to suppress the tra nscriptional activation of the activator protein-1 (AP-1) reporter. Th ese results demonstrate that CD437 can induce apoptosis in NSCLC cells that are resistant to ATRA and that this effect is mediated by a mech anism that may be independent of transactivation of retinoid receptors or transrepression of AP-1. (C) 1997 Wiley-Liss, Inc.