Low dose of lenalidmide and PI3K-mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphomaReportar como inadecuado




Low dose of lenalidmide and PI3K-mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Experimental and Clinical Cancer Research

, 35:52

First Online: 24 March 2016Received: 30 December 2015Accepted: 17 March 2016DOI: 10.1186-s13046-016-0327-x

Cite this article as: Jin, Z., Qing, K., Ouyang, Y. et al. J Exp Clin Cancer Res 2016 35: 52. doi:10.1186-s13046-016-0327-x

Abstract

BackgroundActivated B cell-like subtype of diffuse large B cell lymphoma ABC-DLBCL presents aggressive clinical courses and poor prognosis. Targeting key pathways may raise the possibility of improving clinical outcomes.

MethodsThe synergetic effects were assessed by CCK-8 assay and measured by isobologram analysis. The NVP-Bez235 and lenalidomide cytotoxicity were measured by flow cytometry, Western Blot and si-RNA transfection. The combined treatment inducing tumor regression in vivo was performed in nude mice of OCI-Ly10 xenograft mouse model.

ResultsLow dose of two agents represented significant inhibition of proliferation with CI value < 1. NVP-Bez235 combined with lenalidomide remarkably increased apoptosis through intrinsic pathway by upregulating Bim, Bax and downregulating Bcl-xL. Akt, especially NF-κB, played an important role in the synergetic effects. Cotreatment also induced the cell cycle to be arrested in G0-G1 phase, and decreased S phase by increasing p21 expression, downregulating cyclinA and diminishing CDK2 phosphorylation in Su-DHL2 and OCI-Ly3 but not in OCI-Ly10. Mice treated with NVP-Bez235-lenalidomide represented obvious tumor growth regression and prolonged overall survival.

ConclusionsOur findings demonstrated the synergistic effect of low dose of NVP-Bez235 and lenalidomide in ABC-DLBCL, the underlying mechanism may be multifunctional, involving apoptosis, Akt and NF-κB inactivation and cell cycle arrest. Cotreatment was also effective in vivo. These data pave the way for potential treatment of ABC-DLBCL with combination of NVP-Bez235 and lenalidomide.

KeywordsDiffuse large B cell lymphoma Lenalidomide PI3K-mTOR inhibitor Apoptosis Cell cycle NF-κB First author Zhen Jin, Kai Qing

Co-author Yuan Ouyang, Zhao Liu, Wenfang Wang and Xiaoyang Li.

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Autor: Zhen Jin - Kai Qing - Yuan Ouyang - Zhao Liu - Wenfang Wang - Xiaoyang Li - Zizhen Xu - Junmin Li

Fuente: https://link.springer.com/







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