NEUROBLASTOMA CELL APOPTOSIS INDUCED BY THE SYNTHETIC RETINOID N-(4-HYDROXYPHENYL)RETINAMIDE

N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid with anti-cancer properties and lower toxicity than all-trans retinoic acid (RA). Neuroblastoma cells treated with HPR and observed by fluorescence microscopy showed clear signs of apoptosis, such as chromatin condensation and margination, nuclear fragmentation and the presence of ''apoptotic bodies''. Moreover, measurements on a cell-by-cell basis by the flow-cytometric DNA-content in situ-terminal-deoxinucleotidyl-transferase(TDT) assay showed that apoptosis induced by HPR was dose- and time-dependent and that the fraction of apoptotic cells increased from approximately 15% at 1.25 mu M at 2 days after treatment up to approximately 90% at 5 mu M and 8 days of continuous treatment. Additionally, we found that cells were induced into apoptosis independently from the cell-cycle phase. In contrast, equimolar or higher doses of RA, from 5 mu M to 80 mu M, were able to inhibit growth by differentiation, but failed to induce apoptosis. We conclude that the functional effects of HPR and RA in LA-N-5 neuroblastoma cells are mediated by apoptosis and differentiation respectively, suggesting a potential clinical use of HPR in the management of neuroblastoma patients. (C) 1994 Wiley-Liss, Inc.