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• Guimaraes-Correa, A
• Crawford, L
• Figueiredo, C
• Gimenes, K
• Pinto, L
• Grassi, M
• Feuer, G
• Travassos, L
• Caires, A
• Rodrigues, E
• Marriott, S
• [+] on Google Scholar
• Guimaraes-Correa, A
• Crawford, L
• Figueiredo, C
• Gimenes, K
• Pinto, L
• Grassi, M
• Feuer, G
• Travassos, L
• Caires, A
• Rodrigues, E
• Marriott, S
• [+] on PubMed
• Guimaraes-Correa, A
• Crawford, L
• Figueiredo, C
• Gimenes, K
• Pinto, L
• Grassi, M
• Feuer, G
• Travassos, L
• Caires, A
• Rodrigues, E
• Marriott, S

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Viruses 2011, 3(7), 1041-1058; doi:10.3390/v3071041

Article

C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma

Ana B. Guimaraes-Correa ^1,† , Lindsey B. Crawford ^2,† , Carlos R. Figueiredo ¹ , Karina P. Gimenes ¹ , Lorena A. Pinto ³ , Maria Fernanda Rios Grassi ³ , Gerold Feuer ⁵ , Luiz R. Travassos ¹ , Antonio C.F. Caires ⁴ , Elaine G. Rodrigues ^1,‡  and Susan J. Marriott ^6,‡,*

¹ Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil ² Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA ³ Laboratorio Avançado de Saúde Pública, CPQGM, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia 40296-700, Brazil ⁴ Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi de Cruzes, Mogi das Cruzes, São Paulo 08780-911, Brazil ⁵ Humurine Technologies, Inc., 640 Arrow Highway, La Verne, CA 91750, USA ⁶ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, TX 77030, USA ^† These two authors contributed equally to this work. ^†† These two authors contributed equally to this work.

* Author to whom correspondence should be addressed.

Received: 17 May 2011; in revised form: 17 June 2011 / Accepted: 17 June 2011 / Published: 5 July 2011

(This article belongs to the Special Issue Recent Developments in HTLV Research)

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Abstract: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd₂ [S₍₋₎C², N-dmpa]₂ (μ-dppe)Cl₂}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.

Keywords: cyclopalladated compound; HTLV-1; ATLL; chemotherapy; xenograft model; apoptosis

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