title: The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy.
abstract: Recently, palladium complexes have been extensively studied as cyclization of these complexes by cyclometallation reactions increased their stability making them promising antitumor compounds. In this study, we have investigated apoptosis induced by the Biphosphinic Paladacycle Complex (BPC11) and possible cross talk between apoptosis and autophagy in cell line models of metastatic (Tm5) and non-metastatic (4C11-) melanoma. The BPC11-induced cell death in melanoma involved the lysosomal-mitochondrial axis, which is characterized by LMP, CatB activation and increased Bax protein levels following its translocation to mitochondria. Mitochondrial hyperpolarization, followed by membrane potential dissipation and cleavage of caspase-3, also resulted in cell death after 24 h of incubation. We also found that BPC11-mediated LC3II formation and increased p62 protein levels, suggesting blocked autophagy, probably due to LMP. Interestingly, the treatment of Tm5 and 4C11(-) cells with 3-methyladenine (3-MA), an inhibitor of the initial stage of autophagy, potentiated the effects of BPC11. We conclude that BPC11 is an anti-melanoma agent and that autophagy may be acting as a mechanism of melanoma cells resistance. Also, these data highlight the importance of studies involving autophagy and apoptosis during pre-clinical studies of new drugs with anticancer properties.
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Rafael
authors.initials: R
authors.lastname: Gigli
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Gustavo J S
authors.initials: GJ
authors.lastname: Pereira
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Antunes
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bechara
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Garcia
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Spindola
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Mirian G
authors.initials: MG
authors.lastname: Jasiulionis
authors.affiliation: Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, São Paulo, SP, Brazil.
authors.forename: Antonio C F
authors.initials: AC
authors.lastname: Caires
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Soraya S
authors.initials: SS
authors.lastname: Smaili
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, (UNIFESP), São Paulo, SP, Brazil. Electronic address: claudia.bincoletto@unifesp.br.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bincoletto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry*; D010720:Phosphines / Q000737:chemistry; D021381:Protein Transport / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000610764:BPC11 compound; C494827:Bax protein, mouse; D005296:Ferrous Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; D051028:bcl-2-Associated X Protein; D010165:Palladium; D053148:Caspase 3
keywords: Apoptosis; Autophagy; Cyclopalladated complex; Lysosome-mitochondria axis; Melanoma cells