title: Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis.
abstract: The efficacy of many chemotherapeutic agents can be attenuated by expression of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Mcl-1. Flavopiridol and dinaciclib are cyclin-dependent kinase 7 and 9 inhibitors that transcriptionally inhibit expression of Mcl-1. We have investigated the ability of flavopiridol and dinaciclib to sensitize a panel of leukemia cell lines to vinblastine and paclitaxel. Both drugs acutely sensitized most of the leukemia lines to vinblastine, with 100% apoptosis in 4 h. Furthermore, dinaciclib sensitized freshly isolated chronic lymphocytic leukemia cells to vinblastine. This rapid induction of apoptosis was attributed to vinblastine-mediated activation of JNK because (a) flavopiridol and dinaciclib failed to induce apoptosis when combined with non-JNK activating concentrations of vinblastine; (b) JNK inhibitors suppressed JNK activity and prevented apoptosis; (c) flavopiridol did not potentiate apoptosis induced by paclitaxel which does not activate JNK in these cells; and (d) Jurkat cells failed to activate JNK in response to vinblastine and were not sensitive to combinations of vinblastine and flavopiridol or dinaciclib. The rapid induction of apoptosis by this combination in multiple cell systems but not in normal lymphocytes provides justification for performing a clinical trial to assess the efficacy in patients.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, NH, USA.
authors.forename: Darcy J P
authors.initials: DJ
authors.lastname: Bates
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Salerni
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lowrey
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D007212:Indolizines; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D020298:U937 Cells; D014747:Vinblastine / Q000494:pharmacology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000873:Anthracenes; D000972:Antineoplastic Agents, Phytogenic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D005419:Flavonoids; D007212:Indolizines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011726:Pyridinium Compounds; C432165:pyrazolanthrone; C077990:alvocidib; C553669:dinaciclib; D014747:Vinblastine; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human