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	Mariko Watanabe, Md Zahidunnabi Dewan, Takamitu Okamura, Masataka Sasaki, Kinji Itoh, Masaaki Higashihara, Hideaki Mizoguchi, Mitsuo Honda, Testutaro Sata, Toshiki Watanabe, Naoki Yamamoto, Kazuo Umezawa, Ryouichi Horie
Journal	International journal of cancer (Int J Cancer) Vol. 114 Issue 1 Pg. 32-8 (Mar 10 2005) ISSN: 0020-7136 [Print] United States
PMID	15523684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents BCL2L1 protein, human Bcl2l1 protein, mouse Benzamides CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Calcium-Binding Proteins Cflar protein, mouse Cyclin D Cyclins Cyclohexanones Intracellular Signaling Peptides and Proteins Membrane Glycoproteins NF-kappa B Nerve Tissue Proteins Proto-Oncogene Proteins c-bcl-2 Synaptotagmin I Vascular Endothelial Growth Factor A bcl-X Protein dehydroxymethylepoxyquinomicin Synaptotagmins Cyclin D1 CASP3 protein, human CASP8 protein, human CASP9 protein, human Casp3 protein, mouse Casp8 protein, mouse Casp9 protein, mouse Caspase 3 Caspase 8 Caspase 9 Caspases
Topics	Animals Antineoplastic Agents (pharmacology) Apoptosis (drug effects) Benzamides (pharmacology) CASP8 and FADD-Like Apoptosis Regulating Protein Calcium-Binding Proteins Caspase 3 Caspase 8 Caspase 9 Caspases (metabolism) Cell Line, Tumor Cyclin D Cyclin D1 (metabolism) Cyclins (metabolism) Cyclohexanones (pharmacology) Disease Models, Animal Down-Regulation Enzyme Activation (drug effects) Humans Intracellular Signaling Peptides and Proteins (metabolism) Membrane Glycoproteins Mice Mice, Inbred NOD Mice, SCID Multiple Myeloma (drug therapy, metabolism) NF-kappa B (antagonists & inhibitors) Nerve Tissue Proteins Proto-Oncogene Proteins c-bcl-2 (metabolism) Synaptotagmin I Synaptotagmins Translocation, Genetic (drug effects) Vascular Endothelial Growth Factor A (antagonists & inhibitors) bcl-X Protein

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