N-(4-Hydroxyphenyl)retinamide Activation of a Distinct Pathway Signaling Apoptosis

Extract

The clinical and basic scientific understanding of the role of retinoids in cancer therapy and prevention has seen advances. Retinoids are synthetic and natural analogues of vitamin A [reviewed in (1)]. These compounds are ligands for the retinoid receptors, members of the steroid receptor superfamily (2,3). The biologic effects of retinoids are initiated through liganddependent activation of nuclear retinoid receptors. This interaction leads, in turn, to activation or repression of “target genes,” which results in growth and differentiation effects. The finding that the retinoid N-(4-hydroxyphenyl)retinamide (4HPR) induces apoptosis in cells resistant to all-trans-retinoic acid, a high-affinity ligand for the retinoic acid receptors (RARs) (2,3), has suggested that 4HPR signals through a mechanism independent of the retinoid receptors (4–7). In this issue of the Journal, an article by Oridate et al. (8) links the generation of reactive oxygen species to 4HPR-induced apoptosis in cervical cancer cells. Confirmation that this pathway is active in other cell contexts would provide important evidence for a novel retinoid mechanism signaling apoptosis in human tumor cells.