Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells

Leukemia. 2004 Apr;18(4):747-55. doi: 10.1038/sj.leu.2403295.


A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells. At 20 microM, Roscovitine induced apoptosis in 21 of 28 B-CLL samples and was equally effective in zap-70-positive or -negative samples. Caspase-3 was cleaved in B-CLL cells exposed to Roscovitine and the pancaspase inhibitor z.VAD.fmk-blocked Roscovitine-induced apoptosis. Expression of the proapoptotic protein Bak was increased and Bax cleavage and conformational change was observed in Roscovitine-treated B-CLL cells. Antiapoptotic proteins Mcl-1 and XIAP were downregulated, but the expression of Bcl-2 remained unchanged. In contrast to previous reports in cancer cell lines, Roscovitine treatment was not accompanied by nuclear accumulation of p53. Cyc202 (R-Roscovitine) is in early clinical trials in cancer patients. Given its powerful effects on zap-70-positive and -negative B-CLL cells, but not on normal lymphocytes, Roscovitine might be an attractive drug to be tested in this incurable disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • B-Lymphocytes / drug effects
  • Caspases
  • Cells, Cultured
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Male
  • Middle Aged
  • Protein-Tyrosine Kinases / analysis
  • Purines / pharmacology*
  • Roscovitine
  • Tumor Suppressor Protein p53 / analysis
  • ZAP-70 Protein-Tyrosine Kinase


  • Antineoplastic Agents
  • Purines
  • Tumor Suppressor Protein p53
  • Roscovitine
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Cyclin-Dependent Kinases
  • Caspases