Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells

Cosimo, E. et al. (2013) Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells. Clinical Cancer Research, 19(9), pp. 2393-2405. (doi:10.1158/1078-0432.CCR-12-2170)

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Publisher's URL: http://dx.doi.org/10.1158/1078-0432.CCR-12-2170

Abstract

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Mccaig, Dr Alison and Cosimo, Dr Emilio and Wheadon, Dr Helen and Leach, Dr Michael
Authors: Cosimo, E., McCaig, A. M., Carter-Brzezinski, L. J.M., Wheadon, H., Leach, M. T., Le Ster, K., Berthou, C., Durieu, E., Oumata, N., Galons, H., Meijer, L., and Michie, A. M.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Published Online:26 March 2013
Copyright Holders:Copyright © 2013 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 19(9):2393-2405
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519251Investigating the potential of novel cyclin dependent kinase inhibitors as a novel therapeutic agents in the treatment of chronic lymphocytic leukaemiaAlison MichieScottish Executive Health Department (SEHHD-CSO)CZB/4/748RI CANCER SCIENCES
560201Defining the cellular and molecular characteristics of a quiescent, chemoresistant population of chronic lymphocytic leukaemia cellsEmilio CosimoTenovus-Scotland (TENOVUS)S10/28RI CANCER SCIENCES
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES