title: Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.
abstract: Microtubule targeting agents, such as vinblastine, are usually thought to arrest cells in mitosis and subsequently induce apoptosis. However, they can also cause rapid induction of apoptosis in a cell-cycle phase independent manner. BNC105 is a novel vascular and microtubule disrupting drug that also induces apoptosis rapidly but with markedly increased potency compared to vinca alkaloids and combretastatin A4. BNC105 binds to the colchicine-binding site on tubulin resulting in activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and induction of ATF3 and Noxa leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. Apoptosis induced by BNC105 is dependent upon both JNK activation and Noxa induction. Normal leukocytes and one CLL sample also exhibited JNK activation but not Noxa induction and were resistant to BNC105. This study emphasizes the importance of Noxa and JNK for induction of apoptosis in CLL cells by microtubule targeting drugs, and highlights the potential of BNC105 as a potent therapeutic to treat haematopoietic malignancies.
authors.affiliation: a Department of Medicine , Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.|c Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.
authors.forename: Darcy
authors.initials: D
authors.lastname: Bates
authors.affiliation: b Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.|c Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Feris
authors.affiliation: a Department of Medicine , Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.|c Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
authors.affiliation: b Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.|c Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth , Lebanon , NH , USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D000840:Anisoles / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000840:Anisoles; C552092:BNC 105; D001572:Benzofurans; D013267:Stilbenes; D050257:Tubulin Modulators; D014747:Vinblastine; D048031:JNK Mitogen-Activated Protein Kinases; C058728:fosbretabulin
keywords: Apoptosis; BNC105; Noxa; c-Jun N-terminal kinase; chronic lymphocytic leukemia