Effects of acyclo-retinoic acid and lycopene on activation of the retinoic acid receptor and proliferation of mammary cancer cells.
The biochemical mechanisms underlying the inhibitory effects of lycopene, the main tomato carotenoid, on the growth of cancer cells are largely unknown. It has been hypothesized that lycopene derivatives may act as ligands for a nuclear receptor in analogy to retinoic acid, the hormone derived from beta-carotene. The inhibition of human mammary cancer (MCF-7) cell growth and the transactivation of the retinoic acid receptor (RAR) reporter gene by synthetic acyclo-retinoic acid, the open chain analog of retinoic acid, was compared to the effects of lycopene and retinoic acid in the same systems. Acyclo-retinoic acid activated the DR-5 retinoic acid response element with a approximately 100-fold lower potency than retinoic acid. This effect was independent of cotransfection with the RARalpha receptor. Lycopene exhibited only very modest activity in this system. In contrast to the results from the transactivation studies, acyclo-retinoic acid, retinoic acid, and lycopene 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 interacted with RAR. However, it exhibited low affinity for RAR and a correspondingly low efficacy in activating this receptor, indicating that RAR does not mediate the growth inhibitory effect of the compound. In addition, the concentrations of acyclo-retinoic acid and of lycopene required for inducing inhibition of cell growth were similar, suggesting that acyclo-retinoic acid is unlikely to be the active metabolite of lycopene.
Ben-Dor
A
A
Department of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Nahum
A
A
Danilenko
M
M
Giat
Y
Y
Stahl
W
W
Martin
H D
HD
Emmerich
T
T
Noy
N
N
Levy
J
J
Sharoni
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D002338:Carotenoids / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D000077276:Lycopene; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D025521:Tumor Suppressor Proteins; C431913:acyclo-retinoic acid; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002338:Carotenoids; D000077276:Lycopene