Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model.
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 CLL-like 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.
Fundacion LAIR, Madrid, Spain.
Nerea
N
Rebolleda
Fundacion LAIR, Madrid, Spain.
Ignacio
I
Losada-Fernandez
Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC-UAM, Madrid, Spain.
Gema
G
Perez-Chacon
Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, Universidad Autonoma de Madrid, Madrid, Spain.
Raquel
R
Castejon
Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, Universidad Autonoma de Madrid, Madrid, Spain.
Silvia
S
Rosado
Servicio de Hematologia y Hemoterapia, Hospital Universitario La Paz, Madrid, Spain.
Marta
M
Morado
Laboratorio de Imagen, Plataforma Apoyo a la Investigación, IdiPaz, Hospital Universitario La Paz, Madrid, Spain.
Maria Teresa
MT
Vallejo-Cremades
Fundacion LAIR, Madrid, Spain.
Andrea
A
Martinez
Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, Universidad Autonoma de Madrid, Madrid, Spain.
Juan A
JA
Vargas-Nuñez
Fundacion LAIR, Madrid, Spain.
Paloma
0000-0003-4819-5890
P
Perez-Aciego
D000367:Age Factors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008814:Mice, Inbred NZB; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012402:Rotenone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D012402:Rotenone; D051057:Proto-Oncogene Proteins c-akt; D014740:Vidarabine; C107676:deguelin; C024352:fludarabine