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Food Chem Toxicol. 2019 Feb 7;125:549-561. doi: 10.1016/j.fct.2019.02.013. [Epub ahead of print]

Bixin, an apocarotenoid isolated from Bixa orellana L., sensitizes human melanoma cells to dacarbazine-induced apoptosis through ROS-mediated cytotoxicity.

Author information

1
UMRi CNRS 7266 LIENSs, Université de La Rochelle, 17042 La Rochelle, France.
2
UMRi CNRS 7266 LIENSs, Université de La Rochelle, 17042 La Rochelle, France; Plateforme D'analyse Haute Résolution des Biomolécules, UMR CNRS 7266 LIENSs, 17042 La Rochelle, France.
3
UMR CNRS 8638 Laboratoire de Pharmacognosie, Universté Paris Descartes, 75006 Paris, France.
4
Núcleo de Estudos e Pesquisas de Plantas Medicinais, Universidade Federal Do Vale Do São Francisco, 56306-000 Petrolina, Brazil.
5
UMRi CNRS 7266 LIENSs, Université de La Rochelle, 17042 La Rochelle, France. Electronic address: laurent.picot@univ-lr.fr.

Abstract

Cutaneous melanoma has a high capacity to metastasize and significant resistance to conventional therapeutic protocols, which makes its treatment difficult. The combination of conventional drugs with cytostatic molecules of low toxicity has been shown to be an interesting alternative for sensitization of tumor cells to chemotherapy. In this study, we evaluated the effect of bixin, an abundant apocarotenoid present in Bixa orellana, on the sensitization of human melanoma cells (A2058) to dacarbazine treatment, an anticancer agent clinically used for the therapy of metastatic melanoma. UPLC-DAD-MS/MS analyses of bioactive extracts from B. orellana seeds led to the identification of two new apocarotenoids: 6,8'-diapocarotene-6,8'-dioic acid and 6,7'-diapocarotene-6,7'-dioic acid. After being identified as its major compound, bixin (Z-bixin) was evaluated on A2058 cells expressing the oncogenic BRAF VE600 mutation and resistant to dacarbazine treatment. Bixin promoted growth inhibition, reduced cell migration, induced apoptosis and cell cycle arrest in the G2/M phase. When associated with dacarbazine, bixin restored the sensitivity of A2058 cells to chemotherapy, enhancing its antiproliferative, anti-migratory and pro-apoptotic effects. Combined treatment also induced higher ROS (reactive oxygen species) and MDA (malondialdehyde, a lipid peroxidation marker) generation than monotreatment, suggesting that the oxidative stress caused by bixin contributes significantly to its sensitizing effect. Taken together, these data suggest that bixin exerts intrinsic antimelanoma activity by mechanisms complementary to those of dacarbazine, encouraging its use in combined therapy for cutaneous melanoma treatment.

KEYWORDS:

Annatto; Carotenoids; Dacarbazine; Melanoma; Multidrug resistance

PMID:
30738990
DOI:
10.1016/j.fct.2019.02.013

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