The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy

The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy

Author Gigli, Rafael Autor UNIFESP Google Scholar
Pereira, Gustavo J. S. Autor UNIFESP Google Scholar
Antunes, Fernanda Autor UNIFESP Google Scholar
Bechara, Alexandre Autor UNIFESP Google Scholar
Garcia, Daniel M. Autor UNIFESP Google Scholar
Spindola, Daniel G. Autor UNIFESP Google Scholar
Jasiulionis, Mirian G. Autor UNIFESP Google Scholar
Caires, Antonio C. F. Google Scholar
Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Bincoletto, Claudia Autor UNIFESP Google Scholar
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. (C) 2015 Elsevier Masson SAS. All rights reserved.
Keywords Apoptosis
Lysosome-mitochondria axis
Cyclopalladated complex
Melanoma cellsCathepsin-B Activity
Membrane Permeabilization
Cultured Macrophages
Induced Apoptosis
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 10/51647-6
FAPESP: 12/51215-4
Date 2016
Published in European Journal Of Medicinal Chemistry. Paris, v. 107, p. 245-254, 2016.
ISSN 0223-5234 (Sherpa/Romeo, impact factor)
Publisher Elsevier France-Editions Scientifiques Medicales Elsevier
Extent 245-254
Access rights Closed access
Type Article
Web of Science ID WOS:000366780500019

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