Synergistic activity of deguelin and fludarabine in cells from chronic lymphocytic leukemia patients and in the New Zealand Black murine model
Entity
UAM. Departamento de Medicina; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)Publisher
Public Library of ScienceDate
2016-04-01Citation
10.1371/journal.pone.0154159
PLoS ONE 11.4 (2016): e0154159
ISSN
1932-6203DOI
10.1371/journal.pone.0154159Funded by
This work was supported by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad, PI08/1099, JAV-N; Fondo de Investigaciones Sanitarias, Ministerio de Sanidad PI13/01607, JAV-N; La Caixa P22664, PP-A; and Fundación LAIR P160105, NRProject
Gobierno de España. PI08/1099; Gobierno de España. PI13/01607Editor's Version
http://dx.doi.org/10.1371/journal.pone.0154159Subjects
Cancer cells; Carcinogenesis; AKT; NFκB; Proteins; Inhibitors; MedicinaRights
© 2016 Rebolleda et alAbstract
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLLlike cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.
Files in this item
Google Scholar:Rebolleda, Nerea
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Losada-Fernandez, Ignacio
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Pérez-Chacón, Gema
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Castejon, Raquel
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Rosado, Silvia
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Morado, Marta
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Teresa Vallejo-Cremades, Maria
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Martinez, Andrea
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Vargas Núñez, Juan Antonio
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Perez-Aciego, Paloma
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