Anhydroretinol induces oxidative stress and cell death

The retro-retinoid anhydroretinol (AR), a physiological metabolite of retin ol (vitamin A), induces cell death in multiple in vitro systems. AR-induced cell death is blocked by retinol and its metabolite 14-hydroxy-4,14-retro- retinol AR has been shown also to prevent mammary cancer induced by N-methy l-N-nitrosourea in rats. We report that AR kills cells by generating reacti ve oxygen species. Direct measurements show that the addition of AR to lymp hoblastoid cells increases the intracellular oxidative stress in a time- an d dose-dependent manner. Furthermore, the amount of induced oxidative stres s directly correlates with the number of dying cells. The addition of retin ol, 14-hydroxy-4,14-retro-retinol, or the antioxidant, alpha-tocopherol (vi tamin E), decreases AR-induced oxidative stress and proportionally reduces AR-induced cell death. In contrast, pretreatment with caspase inhibitors, k nown to inhibit apoptosis, has no effect on AR-induced cell death. This is the first demonstration of cellular reactive oxygen species production by a natural retinoid.