- 作者: Samuel Troadec, Melina Blairvacq, Nassima Oumata, Herve Galons, Laurent Meijer, Christian Berthou
- 作者服務機構: Laboratoire de Therapie Cellulaire et Immunobiologie du Cancer, Universite de Bretagne Occidentale, CHRU Morvan, , Brest Cedex, France
- 中文摘要: --
- 英文摘要:
Background:
Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.
Results:
In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid
leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and –resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.
Conclusions:
These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia. - 中文關鍵字: --
- 英文關鍵字: Cyclin-dependent kinases inhibitors, Chronic myeloid leukemia, Cell cycle, Apoptosis, Apoptotic signalling