title: In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas.
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.
  
  
  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 microM for REC, Granta-519 and JeKo-1 cells and 50 microM 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.
authors.affiliation: Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Lacrima
authors.forename: A
authors.initials: A
authors.lastname: Valentini
authors.forename: C
authors.initials: C
authors.lastname: Lambertini
authors.forename: M
authors.initials: M
authors.lastname: Taborelli
authors.forename: A
authors.initials: A
authors.lastname: Rinaldi
authors.forename: E
authors.initials: E
authors.lastname: Zucca
authors.forename: C
authors.initials: C
authors.lastname: Catapano
authors.forename: F
authors.initials: F
authors.lastname: Cavalli
authors.forename: A
authors.initials: A
authors.lastname: Gianella-Borradori
authors.forename: D E
authors.initials: DE
authors.lastname: Maccallum
authors.forename: F
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011687:Purines; D014157:Transcription Factors; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases