HIGHER POTENCY OF N-(4-HYDROXYPHENYL)RETINAMIDE THAN ALL-TRANS-RETINOIC ACID IN INDUCTION OF APOPTOSIS IN NONSMALL CELL LUNG-CANCER CELL-LINES

Most human non-small cell lung cancer (NSCLC) cell lines are refractor y to all-trans-retinoic acid (ATRA). Recently, N-(4-hydroxyphenyl)reti namide (4HPR) was found to induce apoptosis in various tumor cells, In this study, we compared and contrasted the effects of 4HPR and ATRA o n the growth and apoptosis of 10 NSCLC cell lines and normal human bro nchial epithelial (NHBE) cells. All of the cancer cell lines and the N HBE cells were sensitive to 10 mu M 4HPR, and their numbers decreased to <20% of the controls after a 5-day treatment, whereas ATRA decrease d cell numbers to about 50% of the controls in three cell lines and wa s less effective in the rest of the tumor cell lines. ATRA inhibited t he growth of the NHBE cells by 70-80%, 4HPR induced apoptosis in most of the cells, including the ATRA-resistant ones, as evidenced by a DNA fragmentation assay, No correlation was found between growth inhibiti on by 4HPR: and the expression of retinoic acid receptor beta (determi ned by Northern blotting and PCR), p53, or Bcl-2 proteins (analyzed by Western blotting). These results demonstrate that 4HPR is more potent than ATRA in inducing apoptosis in NSCLC cells and suggest that furth er clinical trials for prevention and therapy of NSCLC using 4HPR are warranted.