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

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

Author Guimarães-Corrêa, Ana Beatriz Autor UNIFESP Google Scholar
Crawford, Lindsey B. Google Scholar
Figueiredo, Carlos Rogerio Autor UNIFESP Google Scholar
Gimenes, Karina P. Autor UNIFESP Google Scholar
Pinto, Lorena A. Google Scholar
Rios Grassi, Maria Fernanda Google Scholar
Feuer, Gerold Google Scholar
Travassos, Luiz Rodolpho Autor UNIFESP Google Scholar
Caires, Antonio C. F. Google Scholar
Rodrigues, Elaine Guadelupe Autor UNIFESP Google Scholar
Marriott, Susan J. Google Scholar
Institution Baylor Coll Med
Universidade Federal de São Paulo (UNIFESP)
SUNY Upstate Med Univ
Fundacao Oswaldo Cruz FIOCRUZ
Univ Mogi das Cruzes
Humurine Technol Inc
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(-)C2, N-dmpa](2) (mu-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.
Keywords cyclopalladated compound
HTLV-1
ATLL
chemotherapy
xenograft model
apoptosis
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
National Institutes of Health
New York State Department of Health
Grant number National Institutes of Health: AI078307
National Institutes of Health: CA77371
New York State Department of Health: C023059
New York State Department of Health: N08G-127
Date 2011-07-01
Published in Viruses-basel. Basel: Mdpi Ag, v. 3, n. 7, p. 1041-1058, 2011.
ISSN 1999-4915 (Sherpa/Romeo, impact factor)
Publisher Mdpi Ag
Extent 1041-1058
Origin http://dx.doi.org/10.3390/v3071041
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000293070000005
URI http://repositorio.unifesp.br/handle/11600/33835

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