title: A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.
abstract: Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.
authors.affiliation: The Fourth Department of Internal Medicine, School of Medicine, Kitasato University, Kanagawa, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Md Zahidunnabi
authors.initials: MZ
authors.lastname: Dewan
authors.forename: Takamitu
authors.initials: T
authors.lastname: Okamura
authors.forename: Masataka
authors.initials: M
authors.lastname: Sasaki
authors.forename: Kinji
authors.initials: K
authors.lastname: Itoh
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashihara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Honda
authors.forename: Testutaro
authors.initials: T
authors.lastname: Sata
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Horie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D056741:Cyclin D; D019938:Cyclin D1 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins; D014178:Translocation, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D001549:Benzamides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002135:Calcium-Binding Proteins; C506387:Cflar protein, mouse; D056741:Cyclin D; D016213:Cyclins; D003512:Cyclohexanones; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050863:Synaptotagmin I; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; C464444:dehydroxymethylepoxyquinomicin; D050857:Synaptotagmins; D019938:Cyclin D1; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases