title: C7a, a biphosphinic cyclopalladated compound, efficiently controls the development of a patient-derived xenograft model of adult T cell leukemia/lymphoma.
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 {Pd(2) [S(-)C(2), N-dmpa](2) (μ-dppe)Cl(2)}, 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.
authors: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil.
authors: Ana B
authors: AB
authors: Guimaraes-Correa
authors: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors: Lindsey B
authors: LB
authors: Crawford
authors: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil.
authors: Carlos R
authors: 0000-0003-3680-4070
authors: CR
authors: Figueiredo
authors: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil.
authors: Karina P
authors: KP
authors: Gimenes
authors: Laboratorio Avançado de Saúde Pública, CPQGM, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia 40296-700, Brazil.
authors: Lorena A
authors: LA
authors: Pinto
authors: Laboratorio Avançado de Saúde Pública, CPQGM, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia 40296-700, Brazil.
authors: Maria Fernanda Rios
authors: MFR
authors: Grassi
authors: Humurine Technologies, Inc., 640 Arrow Highway, La Verne, CA 91750, USA.
authors: Gerold
authors: G
authors: Feuer
authors: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil.
authors: Luiz R
authors: LR
authors: Travassos
authors: Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi de Cruzes, Mogi das Cruzes, São Paulo 08780-911, Brazil.
authors: Antonio C F
authors: ACF
authors: Caires
authors: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo 04023-062, Brazil.
authors: Elaine G
authors: EG
authors: Rodrigues
authors: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, TX 77030, USA.
authors: Susan J
authors: SJ
authors: Marriott
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D010165:Palladium / Q000494:pharmacology*; D010632:Pheniramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D023041:Xenograft Model Antitumor Assays
chemical_list: D056831:Coordination Complexes; D010632:Pheniramine; D010165:Palladium; D045304:Cytochromes c