title: The combination of the antiestrogen endoxifen with all-trans-retinoic acid has anti-proliferative and anti-migration effects on melanoma cells without inducing significant toxicity in non-neoplasic cells.
abstract: Melanoma incidence is dramatically increasing and the available treatments beyond partial efficacy have severe side effects. Retinoids are promising anticancer agents, but their clinical use has been limited by their toxicity, although a combination with other agents can possibly generate a therapeutic action at lower dosage. Thus, we investigated the effects of all-trans-retinoic acid combined with the antiestrogen endoxifen on melanoma cell proliferation and the effects were compared with its pro-drug tamoxifen. Moreover, we evaluated the effects of these combinations on non-neoplasic cells and assessed mitochondrial bioenergetic functions, to predict their potential toxicity. Individually, all-trans-retinoic acid and the antiestrogens endoxifen and tamoxifen decreased melanoma cell biomass, cell viability and DNA synthesis, without increased cell death, suggesting that the compounds inhibited cell proliferation. Noteworthy, endoxifen decreased cell proliferation more efficiently than tamoxifen. The combination of endoxifen with all-trans-retinoic acid enhanced the antiproliferative effects of the compounds individually more potently than tamoxifen, which did not enhance the effects induced by all-trans-retinoic acid alone, and blocked cell cycle progression in G1. Moreover, the combination of all-trans-retinoic acid with endoxifen significantly decreased melanoma cells migration, whereas the combination with tamoxifen did not present significant effects. At the concentrations used the compounds did not induce cytotoxicity in non-neoplasic cells and liver mitochondrial bioenergetic function was not affected. Altogether, our results show for the first time that a combined treatment of all-trans-retinoic acid with endoxifen may provide an anti-proliferative and anti-migration effect upon melanoma cells without major toxicity, offering a powerful therapeutic strategy for malignant melanoma.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal.
authors.forename: Mariana P C
authors.initials: MP
authors.lastname: Ribeiro
authors.forename: Filomena S G
authors.initials: FS
authors.lastname: Silva
authors.forename: Joana
authors.initials: J
authors.lastname: Paixão
authors.forename: Armanda E
authors.initials: AE
authors.lastname: Santos
authors.forename: José B A
authors.initials: JB
authors.lastname: Custódio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D008099:Liver / Q000166:cytology; D008297:Male; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D014212:Tretinoin
keywords: All-trans-retinoic acid; Endoxifen; Melanoma; Migration; Proliferation; Tamoxifen