A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.
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.
Watanabe
Mariko
M
The Fourth Department of Internal Medicine, School of Medicine, Kitasato University, Kanagawa, Japan.
Dewan
Md Zahidunnabi
MZ
Okamura
Takamitu
T
Sasaki
Masataka
M
Itoh
Kinji
K
Higashihara
Masaaki
M
Mizoguchi
Hideaki
H
Honda
Mitsuo
M
Sata
Testutaro
T
Watanabe
Toshiki
T
Yamamoto
Naoki
N
Umezawa
Kazuo
K
Horie
Ryouichi
R
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
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