title: Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo.
abstract: Interactions between the proteasome inhibitor carfilzomib and the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Coadministration of very low, marginally toxic carfilzomib concentrations (e.g., 3-4 nmol/L) with minimally lethal vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethality was associated with c-jun-NH,-kinase (JNK) 1/2 activation, increased DNA damage (induction of λH2A.X), and ERK1/2 and AKT1/2 inactivation. Coadministration of carfilzomib and histone deacetylase inhibitors (HDACI) induced a marked increase in reactive oxygen species (ROS) generation and G(2)-M arrest. Significantly, the free radical scavenger tetrakis(4-benzoic acid) porphyrin (TBAP) blocked carfilzomib/HDACI-mediated ROS generation, λH2A.X formation, JNK1/2 activation, and lethality. Genetic (short hairpin RNA) knockdown of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat coadministration resulted in a pronounced reduction in tumor growth compared with single agent treatment in an MCL xenograft model associated with enhanced apoptosis, λH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, MCV Station Box 230, Richmond, VA 23298, USA.
authors.forename: Girija
authors.initials: G
authors.lastname: Dasmahapatra
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lembersky
authors.forename: Minkyeong P
authors.initials: MP
authors.lastname: Son
authors.forename: Elisa
authors.initials: E
authors.lastname: Attkisson
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D000077337:Vorinostat; D000099156:Superoxide Dismutase 2
chemical_list: D020169:Caspases; D048049:Extracellular Signal-Regulated MAP Kinases; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D048670:MAP Kinase Kinase 4; D009842:Oligopeptides; D051058:Oncogene Protein v-akt; D013482:Superoxide Dismutase; D000077337:Vorinostat; D000099156:Superoxide Dismutase 2; C524865:carfilzomib