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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4484-4491.
Prepublished online as a Blood First Edition Paper on February 3, 2005; DOI 10.1182/blood-2004-07-2713.
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NEOPLASIA
A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival
Azra J. Alvi,
Belinda Austen,
Victoria J. Weston,
Christopher Fegan,
David MacCallum,
Athos Gianella-Borradori,
David P. Lane,
Mike Hubank,
Judith E. Powell,
Wenbin Wei,
A. Malcolm R. Taylor,
Paul A. H. Moss, and
Tatjana Stankovic
From the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom; the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom; Cyclacel, Dundee, Scotland, United Kingdom; the Department of Molecular Haematology, Institute of Child Health, University College London, United Kingdom; and the Department of Public Health and Epidemiology, University of Birmingham, United Kingdom.
B-cell chronic lymphocytic leukemia (B-CLL) is a clinically variable disease where mutations in DNA damage response genes ATM or TP53 affect the response to standard therapeutic agents. The in vitro cytotoxicity of a novel cyclin-dependent kinase inhibitor, CYC202, was evaluated in 26 B-CLLs, 11 with mutations in either the ATM or TP53 genes, and compared with that induced by ionizing radiation and fludarabine. CYC202 induced apoptosis within 24 hours of treatment in all 26 analyzed tumor samples independently of ATM and TP53 gene status, whereas 6 of 26 B-CLLs, mostly ATM mutant, showed marked in vitro resistance to fludarabine-induced apoptosis. Compared with B-CLLs, normal T and B lymphocytes treated with CYC202 displayed reduced and delayed apoptosis. Using global gene expression profiling, we found that CYC202 caused a significant down-regulation of genes involved in regulation of transcription, translation, survival, and DNA repair. Furthermore, induction of apoptosis by CYC202 was preceded by inhibition of RNA polymerase II phosphorylation, leading to down-regulation of several prosurvival proteins. We conclude that CYC202 is a potent inducer of apoptosis in B-CLL regardless of the functional status of the p53 pathway, and may be considered as a therapeutic agent to improve the outcome of resistant B-CLL tumors.
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