English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/134340
Título

Potent antimyeloma activity of a novel ERK5/CDK inhibitor

AutorÁlvarez-Fernández, Stela; Ortiz-Ruiz, María Jesús; Parrott, Tracy; Zaknoen, Sara; Ocio, Enrique M.; San Miguel, Jesús F.; Burrows, Francis J.; Esparís-Ogando, Azucena; Pandiella, Atanasio
Fecha de publicación2013
EditorAmerican Association for Cancer Research
CitaciónClinical Cancer Research 19(10): 2677-2687 (2013)
Resumen[Purpose]: To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug. [Experimental Design]: Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02. [Results]: TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1. [Conclusions]: TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients.
URIhttp://hdl.handle.net/10261/134340
DOI10.1158/1078-0432.CCR-12-2118
Identificadoresdoi: 10.1158/1078-0432.CCR-12-2118
issn: 1078-0432
e-issn: 1557-3265
Aparece en las colecciones: (IBMCC) Artículos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
accesoRestringido.pdf15,38 kBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 

Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.