Journal
ANNALS OF ONCOLOGY
Volume 16, Issue 7, Pages 1169-1176Publisher
ELSEVIER
DOI: 10.1093/annonc/mdi217
Keywords
apoptosis; cdk inhibitor; cyclin D1; lymphoma
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Background: Mantle cell lymphoma (MCL) has the worst prognosis of all B-cell lymphomas and has poor response to conventional therapy. It is characterized by the presence of a chromosomal translocation t(11:14) (q13;q32) which results in deregulated cyclin D-1 expression. Since defects in cell cycle regulation and apoptosis are primary events in MCL, small-molecule inhibitors of cdks-cyclins may play an important role in the therapy of this disorder. CYC202 (Seliciclib, R-roscovitine; Cyclacel Ltd., Dundee, UK) is a purine analogue and a selective inhibitor of the cdk2-cyclin E as well as cdk7-cyclin H and cdk9-cyclin T. Materials and methods: The activity of CYC202 was tested in four human MCL cell lines: REC, Granta-519, JeKo-1 and NCEB-1. The effect of CYC202 on the cell cycle and on apoptosis-, cell-cycle- and transcription-regulation-related proteins was assessed. Results: The IC50 was 25 mu M for REC, Granta-519 and JeKo-1 cells and 50 mu M for NCEB-1 cells. CYC202 caused an accumulation of cells in the G(2)-M phase of the cell cycle and apoptosis. CYC202 caused down-regulation of cyclin D-1 and Mcl-1 protein levels, possibly because of the inhibition of transcription elongation. Conclusions: Our data suggest that CYC202 is an active agent in MCL. The concomitant decrease of the phosphorylated and total forms of RNA polymerase II suggests that this could be the main mechanism mediating the biological effects of CYC202 in MCL cells. The drug might represent a new therapeutic agent in this lymphoma subtype.
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