title: Lycopene and beta-carotene induce growth inhibition and proapoptotic effects on ACTH-secreting pituitary adenoma cells.
abstract: Pituitary adenomas comprise approximately 10-15% of intracranial tumors and result in morbidity associated with altered hormonal patterns, therapy and compression of adjacent sella turcica structures. The use of functional foods containing carotenoids contributes to reduce the risk of chronic diseases such as cancer and vascular disorders. In this study, we evaluated the influence of different concentrations of beta-carotene and lycopene on cell viability, colony formation, cell cycle, apoptosis, hormone secretion, intercellular communication and expression of connexin 43, Skp2 and p27(kip1) in ACTH-secreting pituitary adenoma cells, the AtT20 cells, incubated for 48 and 96 h with these carotenoids. We observed a decrease in cell viability caused by the lycopene and beta-carotene treatments; in these conditions, the clonogenic ability of the cells was also significantly decreased. Cell cycle analysis revealed that beta-carotene induced an increase of the cells in S and G2/M phases; furthermore, lycopene increased the proportion of these cells in G0/G1 while decreasing the S and G2/M phases. Also, carotenoids induced apoptosis after 96 h. Lycopene and beta-carotene decreased the secretion of ACTH in AtT20 cells in a dose-dependent manner. Carotenoids blocked the gap junction intercellular communication. In addition, the treatments increased the expression of phosphorylated connexin43. Finally, we also demonstrate decreased expression of S-phase kinase-associated protein 2 (Skp2) and increased expression of p27(kip1) in carotenoid-treated cells. These results show that lycopene and beta-carotene were able to negatively modulate events related to the malignant phenotype of AtT-20 cells, through a mechanism that could involve changes in the expression of connexin 43, Skp2 and p27(kip1); and suggest that these compounds might provide a novel pharmacological approach to the treatment of Cushing's disease.
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.
authors.forename: Natália F
authors.initials: NF
authors.lastname: Haddad
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Teodoro
authors.forename: Felipe
authors.initials: F
authors.lastname: Leite de Oliveira
authors.forename: Nathália
authors.initials: N
authors.lastname: Soares
authors.forename: Rômulo Medina
authors.initials: RM
authors.lastname: de Mattos
authors.forename: Fábio
authors.initials: F
authors.lastname: Hecht
authors.forename: Rômulo Sperduto
authors.initials: RS
authors.lastname: Dezonne
authors.forename: Leandro
authors.initials: L
authors.lastname: Vairo
authors.forename: Regina Coeli Dos Santos
authors.initials: RC
authors.lastname: Goldenberg
authors.forename: Flávia Carvalho Alcântara
authors.initials: FC
authors.lastname: Gomes
authors.forename: Denise Pires
authors.initials: DP
authors.lastname: de Carvalho
authors.forename: Mônica R
authors.initials: MR
authors.lastname: Gadelha
authors.forename: Luiz Eurico
authors.initials: LE
authors.lastname: Nasciutti
authors.forename: Leandro
authors.initials: L
authors.lastname: Miranda-Alves
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002338:Carotenoids / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D000077276:Lycopene; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000473:pathology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D019207:beta Carotene / Q000494:pharmacology*
chemical_list: D018031:Connexin 43; D044786:S-Phase Kinase-Associated Proteins; D019207:beta Carotene; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002338:Carotenoids; D000324:Adrenocorticotropic Hormone; D000077276:Lycopene