title: Synergistic Activity of Carfilzomib and Panobinostat in Multiple Myeloma Cells via Modulation of ROS Generation and ERK1/2.
abstract: Relapse of disease and subsequent resistance to established therapies remain as major challenges in the treatment of multiple myeloma (MM). New therapeutic options are needed for these extensively pretreated patients. To explore an optimized combinational therapy, interactions between the irreversible proteasome inhibitor carfilzomib exhibiting a well-tolerated side-effect profile and histone deacetylase inhibitor (HDACi) panobinostat (LBH589) were examined in MM cells. Coadministration of carfilzomib and LBH589 led to a synergistic inhibition of proliferation in MM cells. Further studies showed that the combined treatment synergistically increased mitochondrial injury, caspase activation, and apoptosis in MM cells. Lethality of the carfilzomib/LBH589 combination was associated with the reactive oxygen species (ROS) generation and ERK1/2 inactivation. In addition, the free radical scavenger N-acetylcysteine (NAC) could block carfilzomib and LBH589-induced oxidative stress and the subsequent apoptosis. Together, these findings argue that the strategy of combining carfilzomib and LBH589 warrants attention in MM.
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Ruixue
authors.identifier: 0000-0001-7773-3374
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Gongwen
authors.initials: G
authors.lastname: Ai
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Huiqun
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D000077767:Panobinostat; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D006877:Hydroxamic Acids; D007211:Indoles; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C524865:carfilzomib; D000077767:Panobinostat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases