A novel NF-?B inhibitor DHMEQ selectively targets constitutive NF-?B activity and induces apoptosis of multiple myeloma cellsin vitro andin vivo

Autor: Naoki Yamamoto, Masaaki Higashihara, Masataka Sasaki, Md. Zahidunnabi Dewan, Mitsuo Honda, Mariko Watanabe, Hideaki Mizoguchi, Kazuo Umezawa, Kinji Itoh, Toshiki Watanabe, Takamitu Okamura, Ryouichi Horie, Testutaro Sata
Rok vydání: 2005
Předmět:
Vascular Endothelial Growth Factor A
Cancer Research
CASP8 and FADD-Like Apoptosis Regulating Protein
Apoptosis
Mice
SCID
Translocation
Genetic
Mice
Synaptotagmins
chemistry.chemical_compound
Mice
Inbred NOD
Cyclin D1
Caspase
Caspase 8
Membrane Glycoproteins
biology
Caspase 3
Intracellular Signaling Peptides and Proteins
NF-kappa B
Caspase 9
Vascular endothelial growth factor
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
Caspases
Synaptotagmin I
Benzamides
Multiple Myeloma
medicine.medical_specialty
Programmed cell death
bcl-X Protein
Down-Regulation
Antineoplastic Agents
Nerve Tissue Proteins
Downregulation and upregulation
Cell Line
Tumor
Cyclin D
Cyclins
Internal medicine
medicine
Animals
Humans
Autocrine signalling
Cyclohexanones
Calcium-Binding Proteins
NF-κB
Enzyme Activation
Disease Models
Animal
Endocrinology
chemistry
biology.protein
Cancer research
Bone marrow
Zdroj: International Journal of Cancer. 114:32-38
ISSN: 1097-0215
0020-7136
DOI: 10.1002/ijc.20688
Popis: 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.
Databáze: OpenAIRE
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