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A novel NF-κB inhibitor DHMEQ selectively targets constitutive NF-κB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo

✍ Scribed by 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

Publisher
John Wiley and Sons
Year
2005
Tongue
French
Weight
453 KB
Volume
114
Category
Article
ISSN
0020-7136

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✦ Synopsis

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.

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