title: Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines.
abstract: 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.
authors.affiliation: Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, 29609, Brest Cedex, France. samuel.troadec@univ-brest.fr.|Current address: Institut Universitaire Technologique, Département de Génie Biologique, Brest, France. samuel.troadec@univ-brest.fr.
authors.forename: Samuel
authors.initials: S
authors.lastname: Troadec
authors.affiliation: "Protein Phosphorylation and Human Diseases" Group, CNRS, USR3151, Station Biologique, Roscoff, France. melina.blairvacq@gmail.com.
authors.forename: Mélina
authors.initials: M
authors.lastname: Blairvacq
authors.affiliation: ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, Roscoff, France. oumata@manros-therapeutics.com.
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.affiliation: Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes UMR-S 1022 Inserm, 4 avenue de l'Observatoire, Paris, France. herve.galons@univ-paris5.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.affiliation: ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, Roscoff, France. meijer@manros-therapeutics.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, 29609, Brest Cedex, France. cberthou@univ-brest.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: C107489:BIRC5 protein, human; C532131:CR8 compound; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000068877:Imatinib Mesylate; D018844:Cyclin-Dependent Kinases