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Title: Palladacycle (BPC) antitumour activity against resistant and metastatic cell lines: the relationship with cytosolic calcium mobilisation and cathepsin B activity
Authors: Bechara, Alexandre [UNIFESP]
Barbosa, Christiano M. V. [UNIFESP]
Paredes-Gamero, Edgar J. [UNIFESP]
Garcia, Daniel M. [UNIFESP]
Silva, Luis S. [UNIFESP]
Matsuo, Alisson L. [UNIFESP]
Nascimento, Fabio D.
Rodrigues, Elaine G. [UNIFESP]
Caires, Antonio C. F.
Smaili, Soraya Soubhi [UNIFESP]
Bincoletto, Claudia [UNIFESP]
Universidade Federal de São Paulo (UNIFESP)
Univ Bandeirante São Paulo UNIBAN
Univ Mogi das Cruzes
Keywords: Cytotoxicity
Biphosphinic Palladacycle Complex
Anticancer compounds
Calcium signalling
Lysosomal Membrane Permeabilisation
Cathepsin B
Issue Date: 22-May-2014
Publisher: Elsevier B.V.
Citation: European Journal of Medicinal Chemistry. Paris: Elsevier France-editions Scientifiques Medicales Elsevier, v. 79, p. 24-33, 2014.
Abstract: The search for new compounds that induce p53-independent apoptosis is the focus of many studies in cancer biology because these compounds could be more specific and would overcome chemotherapy resistance. in this study, we evaluated the in vitro antitumour activity of a Biphosphinic Palladacycle Complex (BPC) and extended preclinical studies to an in vivo model. Saos-2 cells, a p53-null human osteosarcoma drug-resistant cell line, were treated with BPC in the presence or absence of a cathepsin B inhibitor and a calcium chelator (CA074 and BAPTA-AM, respectively), and several parameters related to apoptosis were evaluated. Preclinical studies were performed with mice that were intravenously inoculated with murine melanoma Bl6F10-Nex2 cells and treated intraperitoneally (i.p.) with BPC (8 mg/kg/ day) for ten consecutive days, when lung metastatic nodules were counted. in vitro data show that BPC induces cell death in Saos-2 cells mainly by apoptosis, which was accompanied by the effector caspase-3 activation. These events are most likely related to Bax translocation and increased cytosolic calcium mobilisation, mainly from intracellular compartments. Lysosomal Membrane Permeabilisation (LMP) was also observed after 12 h of BPC exposure. Interestingly, BAPTA-AM and CA074 significantly decreased BPC cytotoxicity, suggesting that both calcium and cathepsin B are required for BPC antitumour activity. in vivo studies demonstrated that BPC protects mice against murine metastatic melanoma. in conclusion, BPC complex is an effective anticancer compound against metastatic murine melanoma. This complex is cytotoxic to the drug-resistant osteosarcoma Saos-2 human tumour cells by inducing apoptosis triggered by calcium signalling and a lysosomal-dependent pathway. (C) 2014 Elsevier Masson SAS. All rights reserved.
ISSN: 0223-5234
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