title: Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs.
abstract: Marizomib (NPI-0052) is a naturally derived irreversible proteasome inhibitor that potently induces apoptosis via a caspase-8 and ROS-dependent mechanism in leukemia cells. We aim to understand the relationship between the irreversible inhibition of the proteasome and induction of cell death in leukemia cells by using analogs of marizomib that display reversible and irreversible properties. We highlight the importance of sustained inhibition of at least two proteasome activities as being key permissive events for the induction of the apoptotic process in leukemia cells. These data provide the basis for the development of new approaches to generate more effective anti-proteasome therapies.
authors.affiliation: Department of Pediatrics Research, Children's Cancer Hospital at M.D. Anderson, University of Texas M.D. Anderson Cancer Center, Houston, United States.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Miller
authors.forename: Christa A
authors.initials: CA
authors.lastname: Manton
authors.forename: Randal
authors.initials: R
authors.lastname: Hale
authors.forename: LaKeisha
authors.initials: L
authors.lastname: Debose
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Macherla
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Potts
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007783:Lactones; D011480:Protease Inhibitors; D011758:Pyrroles; D017382:Reactive Oxygen Species; C475865:marizomib; D053181:Caspase 8