XIAP
Xiap
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.Leukemia
advance online publication, 19 February 2004; doi:10.1038/sj.leu.2403295
PMID: 14973497 [PubMed - as supplied by publisher