Effects of acyclo-retinoic acid and lycopene on activation of the retinoicacid receptor and proliferation of mammary cancer cells

The biochemical mechanisms underlying the inhibitory effects of lycopene, t he main tomato carotenoid, on the growth of cancer cells are largely unknow n. It has been hypothesized that lycopene derivatives may act as ligands fo r a nuclear receptor in analogy to retinoic acid, the hormone derived from S-carotene. The inhibition of human mammary cancer (MCF-7) cell growth and the transactivation of the retinoic acid receptor (RAR) reporter gene by sy nthetic acyclo-retinoic acid, the open chain analog of retinoic acid, was c ompared to the effects of lycopene and retinoic acid in the same systems. A cyclo-retinoic acid activated the DR-5 retinoic acid response element with a similar to 100-fold lower potency than retinoic acid. This effect was ind ependent of cotransfection with the RAR alpha receptor. Lycopene exhibited only very modest activity in this system. In contrast to the results from t he transactivation studies, acyclo-retinoic acid, retinoic acid, and lycope ne inhibited cell growth with a similar potency. Preincubation with each of the three compounds slowed down cell cycle progression from G1 to S phase. In summary, acyclo-retinoic acid inhibited cancer cell growth and interact ed with RAR. However, it exhibited low affinity for RAR and a corresponding ly low efficacy in activating this receptor, indicating that RAR does not m ediate the growth inhibitory effect of the compound. In addition, the conce ntrations of acyclo-retinoic acid and of lycopene required for inducing inh ibition of cell growth were similar, suggesting that acyclo-retinoic acid i s unlikely to be the active metabolite of lycopene. (C) 2001 Academic Press .