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Annals of Oncology Advance Access published online on April 25, 2005
Annals of Oncology, doi:10.1093/annonc/mdi217
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© 2005 European Society for Medical Oncology
Received November 29, 2004
Revised February 8, 2005
Accepted February 8, 2005

Original article

In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas

K. Lacrima 1, A. Valentini 1, C. Lambertini 1, M. Taborelli 1, A. Rinaldi 1, E. Zucca 2, C. Catapano 1, F. Cavalli 3, A. Gianella-Borradori 4, D. E. MacCallum 4, and F. Bertoni 5*

1 Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland and
2 Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
3 Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland and 2Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
4 Cyclacel Ltd, Dundee, Scotland, UK;
5 Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland and 4Experimental Haematology, St Bartholomew's Hospital and The London Hospital, London, UK

* To whom correspondence should be addressed.
F. Bertoni, E-mail: frbertoni{at}mac.com


  Abstract

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 D1 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 µM for REC, Granta-519 and JeKo-1 cells and 50 µM for NCEB-1 cells. CYC202 caused an accumulation of cells in the G2-M phase of the cell cycle and apoptosis. CYC202 caused down-regulation of cyclin D1 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.

Keywords: apoptosis; cdk inhibitor; cyclin D1; lymphoma.

{dagger}K. Lacrima and A. Valentini contributed equally to this work.


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