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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Michie, Professor Alison and Mccaig, Dr Alison and Cosimo, Dr Emilio and Wheadon, Professor 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 > School 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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