A. R. Agner, L. F. Barbisan, C. Scolastici, and D. M. Salvadori, Absence of carcinogenic and anticarcinogenic effects of annatto in the rat liver medium-term assay, Food Chem, 2004.

. Toxicol, , vol.42, pp.1687-1693

M. S. Ahamad, S. Siddiqui, A. Jafri, S. Ahmad, M. Afzal et al., Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest, PLoS One, vol.9, 2014.

,

A. Anantharaman, H. Hemachandran, S. Mohan, D. Manikoth-ayyathan, D. T. Kumar et al., Induction of apoptosis by apocarotenoids in B16 melanoma cells through ROS-mediated mitochondrial-dependent pathway, J. Funct. Foods, vol.20, pp.346-357, 2016.

A. R. Bautista, E. L. Moreira, M. S. Batista, M. S. Miranda, and I. C. Gomes, Subacute toxicity assessment of annatto in rat, Food Chem. Toxicol, vol.42, pp.625-629, 2004.

,

S. Bhatia, S. S. Tykodi, and J. A. Thompson, Treatment of metastatic melanoma: an overview, Oncology, vol.23, pp.488-96, 2009.

R. Chakraborty, C. N. Wieland, and N. I. Comfere, Molecular targeted therapies in metastatic melanoma, Pharmgenomics. Pers. Med, vol.6, pp.49-56, 2013.

,

P. B. Chapman, A. Hauschild, C. Robert, J. B. Haanen, P. Ascierto et al., Improved survival with vemurafenic in melanoma with BRAF V600E mutation, 2011.

, Eng J Med, vol.364, pp.2507-2516

R. C. Chisté, F. Yamashita, F. C. Gozzo, and A. Z. Mercadante, Simultaneous extraction and analysis by high performance liquid chromatography coupled to diode array and mass spectrometric detectors of bixin and phenolic compounds from annatto seeds, J. Chromatogr. A, vol.1218, pp.57-63, 2011.

J. Cisilotto, L. P. Sandjo, L. G. Faqueti, H. Fernandes, D. Joppi et al., Cytotoxicity mechanisms in melanoma cells and UPLC-QTOF/MS2chemical characterization of two Brazilian stingless bee propolis: Uncommon presence of piperidinic alkaloids, J. Pharm. Biomed. Anal, vol.149, pp.502-511, 2018.

,

D. Dankort, D. P. Curley, R. A. Cartlidge, B. Nelson, A. N. Karnezis et al., BrafV600E cooperates with Pten loss to induce metastatic melanoma, Nat. Genet, vol.41, pp.544-552, 2009.

,

R. G. De-oliveira-júnior, C. Adrielly, A. F. Da-silva-almeida, J. R. Grougnet, R. Thiéry et al., Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms, Fitoterapia, vol.129, pp.383-400, 2018.

S. Eghbaliferiz and M. Iranshahi, Prooxidant Activity of Polyphenols, Flavonoids, Anthocyanins and Carotenoids: Updated Review of Mechanisms and Catalyzing Metals, 2016.

, Phyther. Res, vol.1391, pp.1379-1391

K. T. Flaherty and G. Mcarthur, BRAF, a target in melanoma, Cancer, vol.116, pp.4902-4913, 2010.

C. Garbe, P. Radny, R. Linse, R. Dummer, R. Gutzmer et al., Adjuvant lowdose interferon ?2a with or without dacarbazine compared with surgery alone: A prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis, Ann. Oncol, vol.19, pp.1195-1201, 2008.

,

D. Grotto, L. Santa-maria, J. Valentini, C. Paniz, G. Schmitt et al., Importance of the lipid peroxidation biomarkers and methodological aspects for malondialdehyde quantification, Quim. Nova, vol.32, pp.169-174, 2009.

,

S. Jin, P. S. Mishra-kalyani, and R. Sridhara, Unresectable and Metastatic Melanoma of the Skin : Literature Review of Clinical Trials and Efficacy Endpoints Since, 2000.

I. J. Jondiko and G. Pattenden, Terpenoids and an apocarotenoid from seeds of Bixa orellana, Phytochemistry, vol.28, pp.3159-3162, 1989.

C. Juin, R. G. Oliveira-junior, . De, A. Fleury, C. Oudinet et al., Zeaxanthin from Porphyridium purpureum induces apoptosis in human melanoma cells expressing the oncogenic BRAF V600E mutation and sensitizes them to the BRAF inhibitor vemurafenib, Brazilian J. Pharmacogn, vol.28, pp.457-467, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01868622

,

C. Locatelli, F. B. Filippin-monteiro, and T. B. Creczynski-pasa, Current Therapies and New Pharmacologic Targets for Metastatic Melanoma, Recent Adv. Biol. Ther. Manag. Melanoma, 2013.

R. M. Mackie, A. Hauschild, and A. M. Eggermont, Epidemiology of invasive cutaneous melanoma, Ann. Oncol, vol.20, pp.1-7, 2009.

A. Z. Mercadante, A. Steck, and H. Pfander, Isolation and structure elucidation of minor carotenoids from annatto (Bixa orellana L.) seeds, Phytochemistry, vol.46, pp.1379-1383, 1997.

, , pp.462-469

S. Mohan, P. Rajendra, H. Hemachandran, and P. Kumar, Prospects and progress in the production of valuable carotenoids : Insights from metabolic engineering , synthetic biology , and computational approaches 266, pp.89-101, 2018.

,

T. Mosmann, Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays, J. Immunol. Methods, vol.65, pp.55-63, 1983.

, , pp.90303-90307

R. Mouawad, M. Sebert, J. Michels, J. Bloch, J. P. Spano et al., Treatment for metastatic malignant melanoma: Old drugs and new strategies, Crit. Rev. Oncol, 2010.

. Hematol, , vol.74, pp.27-39

A. Nagao, Functions and Actions of Retinoids and Carotenoids : Building on the Vision of James Allen Olson Carotene Oxygenases : A New Family of Double Bond Cleavage Enzymes, Am. Soc. Nutr. Sci, pp.246-250, 2004.

F. J. Paumgartten, R. R. De-carvalho, I. B. Araujo, F. M. Pinto, O. O. Borges et al., Evaluation of the developmental toxicity of annatto in the rat, Food Chem. Toxicol, vol.40, issue.02, pp.133-136, 2002.

R. Priya, P. Sneha, R. R. Madrid, C. , and G. P. , Molecular Modeling and Dynamic Simulation of Arabidopsis Thaliana Carotenoid Cleavage Dioxygenase Gene: A Comparison with Bixa orellana and Crocus Sativus 2721, pp.2712-2721, 2017.

,

D. Raddatz-mota, L. J. Pérez-flores, F. Carrari, J. A. Mendoza-espinoza, F. D. De-león-sánchez et al., Achiote (Bixa orellana L.): a natural source of pigment and vitamin E, J. Food Sci. Technol, vol.54, pp.1729-1741, 2017.

J. Rehbein, B. Dietrich, M. D. Grynbaum, P. Hentschel, K. Holtin et al., Characterization of bixin by LC-MS and LC-NMR, J. Sep. Sci, vol.30, pp.2382-2390, 2007.

D. Ribeiro, M. Freitas, A. M. Silva, F. Carvalho, and E. Fernandes, Antioxidant and pro-oxidant activities of carotenoids and their oxidation products, Food Chem. Toxicol, vol.120, pp.681-699, 2018.

A. Rios, O. De, A. Z. Mercadante, and C. D. Borsarelli, Triplet state energy of the carotenoid bixin determined by photoacoustic calorimetry, Dye. Pigment, vol.74, pp.561-565, 2007.

,

A. D. Rios, C. D. Borsarelli, and A. Z. Mercadante, Thermal degradation kinetics of bixin in an aqueous model system, J. Agric. Food Chem, vol.53, pp.2307-2311, 2005.

,

R. Rivera-madrid, M. Aguilar-espinosa, Y. Cárdenas-conejo, and L. E. Garza-caligaris, Carotenoid Derivates in Achiote (Bixa orellana) Seeds: Synthesis and Health Promoting Properties, Front. Plant Sci, vol.7, pp.1-7, 2016.

L. M. Rodrigues, S. C. Alcázar-alay, A. J. Petenate, and M. A. Meireles, Bixin extraction from defatted annatto seeds, Comptes Rendus Chim, 2014.

,

G. Santos, M. Almeida, L. Antunes, and M. Bianchi, Effect of bixin on DNA damage and cell death induced by doxorubicin in HL60 cell line, Hum. Exp. Toxicol, vol.35, pp.1319-1327, 2016.

,

. Shahid-ul-islam, L. J. Rather, and F. Mohammad, Phytochemistry, biological activities and potential of annatto in natural colorant production for industrial applications -A review, 2016.

, J. Adv. Res, vol.7, pp.499-514

J. A. Sosman and I. Puzanov, Molecular targets in melanoma from angiogenesis to apoptosis, Clin. Cancer Res, vol.12, pp.2376-2384, 2006.

S. J. Stohs, Safety and efficacy of Bixa orellana (achiote, annatto) leaf extracts, Phyther. Res, vol.28, pp.956-960, 2014.

S. Tay-agbozo, S. Street, and L. Kispert, Journal of Photochemistry & Photobiology , B : Biology The carotenoid Bixin found to exhibit the highest measured carotenoid oxidation potential to date consistent with its practical protective use in cosmetics, 2018.

, J. Photochem. Photobiol. B Biol, vol.186, pp.1-8

,

L. Tentori, P. M. Lacal, and G. Graziani, Challenging resistance mechanisms to therapies for metastatic melanoma, Trends Pharmacol. Sci, vol.34, pp.656-666, 2013.

,

J. D. Tibodeau, C. R. Isham, and K. C. Bible, Annatto constituent cis-bixin has selective antimyeloma effects mediated by oxidative stress and associated with inhibition of thioredoxin and thioredoxin reductase, Antioxid. Redox Signal, vol.13, pp.987-97, 2010.

,

L. Tocchini and A. Z. Mercadante, Extração E Determinação, Por Clae, De Bixina E Norbixina Em Coloríficos, Ciência e Tecnol. Aliment, vol.21, pp.310-313, 2001.

,

D. Vilar, A. De, M. S. Vilar, A. De, T. F. De-lima-e-moura et al., Traditional uses, chemical constituents, and biological activities of, Bixa orellana L.: a review. Sci. World J, vol.857292, pp.1-11, 2014.

B. S. Vinod, T. T. Maliekal, and R. J. Anto, Phytochemicals As Chemosensitizers: From Molecular Mechanism to Clinical Significance, Antioxid. Redox Signal, vol.18, pp.1307-1348, 2013.

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