Chemoprevention of Skin Carcinogenesis by Phenylretinamides: Retinoid Receptor–Independent Tumor Suppression

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Abstract
Fenretinide [N-(4-hydroxyphenyl)retinamide or 4-HPR] is a synthetic retinoid analogue with antitumor and chemopreventive activities. N-(4-Methoxyphenyl)retinamide (4-MPR) is the most abundant metabolite of 4-HPR detected in human serum following 4-HPR therapy. We have shown in in vitro studies that 4-HPR and 4-MPR can act independent of the classic nuclear retinoid receptor pathway and that 4-HPR, but not 4-MPR, can also activate nuclear retinoid receptors. In this study, we have compared the chemopreventive effects of topically applied 4-HPR and 4-MPR with the primary biologically active retinoid, all-trans retinoic acid (ATRA), in vivo in the mouse skin two-stage chemical carcinogenesis model. All three retinoids suppressed tumor formation but the effect of 4-HPR and 4-MPR, and not of ATRA, was sustained after their discontinuation. The tumor-suppressive effects of 4-HPR and 4-MPR were quantitatively and qualitatively similar, suggesting that the two may be acting through the same retinoid receptor–independent mechanism(s). We further explored this effect in vitro by analyzing primary cultures of mouse keratinocytes treated with the same retinoids. All three could induce apoptosis with a 48-hour treatment and only ATRA and 4-HPR induced an accumulation of cells in the G1 phase of the cell cycle. This finding is consistent with our previous results showing that the effects of phenylretinamides on the cell cycle are retinoid receptor dependent whereas apoptosis induction is not. A microarray-based comparison of gene expression profiles for mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and TPA + 4-HPR or TPA + 4-MPR reveals a high degree of coincidence between the genes regulated by the two phenylretinamides. We propose that 4-HPR may exert therapeutic and chemopreventive effects by acting primarily through a retinoid receptor–independent mechanism(s) and that 4-MPR may contribute to the therapeutic effect of 4-HPR by acting through the same retinoid receptor–independent mechanism(s).