title: Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process.
abstract: Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML.
authors.affiliation: Department of Medicine, Institute of Molecular Medicine and Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA. mrahmani@vcu.edu
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Mandy Mayo
authors.initials: MM
authors.lastname: Aust
authors.forename: Elisa
authors.initials: E
authors.lastname: Attkisson
authors.forename: David C
authors.initials: DC
authors.lastname: Williams
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferreira-Gonzalez
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001557:Benzenesulfonates; D007211:Indoles; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; C520962:obatoclax