Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. However, many lung cancer cell lines are resistant to the growth inhibitory effects of all-trans-retinoic acid (ATRA). Recently, we found that a new synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2naphthalene carboxylic acid (CD437), which binds selectively to nuclear RA receptor g, was the most effective inhibitor of the growth of human non-small cell lung carcinoma (NSCLC) cells among 37 retinoids tested. After a 4-day treatment with CD437 the growth of 8 NSCLC cell lines was inhibited with an IC 50 ranging from 0.13 to 0.53 mM. In contrast, ATRA failed to inhibit the growth of any of these cell lines by more than 43% after a 7-day treatment even at 10 mM. 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 apoptosis. Two retinoids, CD2366 and CD2665, which are antagonists of nuclear retinoid receptor activation, failed to inhibit the effect of CD437 on the growth of the NSCLC cell lines. CD437 failed to suppress the transcriptional activation of the activator protein-1 (AP-1) reporter. These results demonstrate that CD437 can induce apoptosis in NSCLC cells that are resistant to ATRA and that this effect is mediated by a mechanism that may be independent of transactivation of retinoid receptors or transrepression of AP-1.