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.