Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthal ene carboxylic acid (CD437) has been shown to induce apoptosis in various t umor cell lines including human non-small cell lung carcinoma (NSCLC) cells , which are resistant to the natural all-trans retinoic acid and to many sy nthetic receptor-selective retinoids, Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid rec eptors, In the present study, we analysed the mechanisms by which CD437 ind uces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H 1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis, CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 c ells, The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-in duced CPP32-like caspase activation and apoptosis in both cell lines, CD437 induced the expression of the p53 gene and its target genes, p21, Bas, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induc ed apoptosis is more extensive in NSCLC cells that express wild-type p53, p ossibly due to the involvement of the p53 regulated genes Killer/DR5, and B ar although CD437 can also induce apoptosis by means of a p53-independent m echanism. Both pathways of CD437-induced apoptosis appear to involve activa tion of CPP32-like caspase.