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.
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.
Alvi
Azra J
AJ
Cancer Research UK Institute for Cancer Studies, University of Birmingham, B15 2TT, United Kingdom.
Austen
Belinda
B
Weston
Victoria J
VJ
Fegan
Christopher
C
MacCallum
David
D
Gianella-Borradori
Athos
A
Lane
David P
DP
Hubank
Mike
M
Powell
Judith E
JE
Wei
Wenbin
W
Taylor
A Malcolm R
AM
Moss
Paul A H
PA
Stankovic
Tatjana
T
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004341:Drug Evaluation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011687:Purines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D000077546:Roscovitine; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011687:Purines; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077546:Roscovitine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II