Palladacycle (BPC) antitumour activity against resistant and metastatic cell lines: the relationship with cytosolic calcium mobilisation and cathepsin B activity.
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 B16F10-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.
Departamento de Farmacologia, EPM, Universidade Federal de São Paulo (UNIFESP), Rua Três de maio, 100 - 2nd Floor, Vila Clementino, São Paulo, SP, Brazil.
Alexandre
A
Bechara
Departamento de Biofísica, EPM, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Christiano M V
CM
Barbosa
Departamento de Biofísica, EPM, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Edgar J
EJ
Paredes-Gamero
Departamento de Farmacologia, EPM, Universidade Federal de São Paulo (UNIFESP), Rua Três de maio, 100 - 2nd Floor, Vila Clementino, São Paulo, SP, Brazil.
Daniel M
DM
Garcia
Unidade de Oncologia Experimental (UNONEX), EPM, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Luís S
LS
Silva
Unidade de Oncologia Experimental (UNONEX), EPM, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Alisson L
AL
Matsuo
Universidade Bandeirante de São Paulo (UNIBAN), São Paulo, SP, Brazil.
Fábio D
FD
Nascimento
Unidade de Oncologia Experimental (UNONEX), EPM, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Elaine G
EG
Rodrigues
Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil.
Antonio C F
AC
Caires
Departamento de Farmacologia, EPM, Universidade Federal de São Paulo (UNIFESP), Rua Três de maio, 100 - 2nd Floor, Vila Clementino, São Paulo, SP, Brazil.
Soraya S
SS
Smaili
Departamento de Farmacologia, EPM, Universidade Federal de São Paulo (UNIFESP), Rua Três de maio, 100 - 2nd Floor, Vila Clementino, São Paulo, SP, Brazil. Electronic address: claudia.bincoletto@unifesp.br.
Claudia
C
Bincoletto
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C534987:biphosphinic palladacycle complex; D053148:Caspase 3; D002401:Cathepsin B; D002118:Calcium
Anticancer compounds; Biphosphinic Palladacycle Complex; Calcium signalling; Cathepsin B; Cytotoxicity; Lysosomal Membrane Permeabilisation