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Open Access Research article

A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

Fabiana A Serrano1, Alisson L Matsuo1, Priscila T Monteforte2, Alexandre Bechara2, Soraya S Smaili2, Débora P Santana3, Tiago Rodrigues4, Felipe V Pereira1, Luis S Silva5, Joel Machado6, Edson L Santos7, João B Pesquero8, Rafael M Martins9, Luiz R Travassos1, Antonio CF Caires3 and Elaine G Rodrigues1*

Author Affiliations

1 Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil

2 Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil

3 Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, São Paulo, Brazil

4 Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, São Paulo, Brazil

5 Disciplina de Biologia Celular, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil

6 Departamento de Ciências Biológicas, Universidade Federal de São Paulo, São Paulo, Brazil

7 Faculdade de Ciências Biológicas e Ambientais, Universidade Federal da Grande Dourados, Mato Grosso do Sul, Brazil

8 Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil

9 Disciplina de Parasitologia, Departamento de Microbiologia, Imunologia e Parasitologia, Unversidade Federal de São Paulo, São Paulo, Brazil

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BMC Cancer 2011, 11:296  doi:10.1186/1471-2407-11-296

Published: 14 July 2011

Abstract

Background

Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd2 [S(-)C2, N-dmpa]2 (μ-dppe)Cl2} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.

Methods

B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a.

Results

Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.

Conclusions

The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.