Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines

• Published in: Journal of biomedical science Vol. 22; no. 1; p. 57
• Main Authors: Troadec, Samuel, Blairvacq, Mélina, Oumata, Nassima, Galons, Hervé, Meijer, Laurent, Berthou, Christian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.07.2015; BioMed Central
• Subjects: Analysis; Apoptosis; Apoptosis - drug effects; Cancer; Care and treatment; Cell Proliferation - drug effects; Chemotherapy; Chronic myeloid leukemia; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; Development and progression; Drug Resistance, Neoplasm - genetics; Drug therapy; Gene Expression Regulation, Leukemic - drug effects; Humans; Imatinib Mesylate - administration & dosage; Inhibitor of Apoptosis Proteins - biosynthesis; K562 Cells; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis; Oncology, Experimental; Protein Kinase Inhibitors - administration & dosage; Purines - administration & dosage; Pyridines - administration & dosage; Signal Transduction - drug effects; X-Linked Inhibitor of Apoptosis Protein - biosynthesis; France
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-015-0163-x

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. 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. These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.