The novel IκB kinase β inhibitor IMD-0560 prevents bone invasion by oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) cells display significantly augmented nuclear factor-κB (NF-κB) activity, and inhibiting this activity suppresses malignant tumor characteristics. Thus, we evaluated the effect of IMD-0560, a novel inhibitor of IκB kinase (IKK) β that is under assessment in a clinical trial of rheumatoid arthritis, on bone invasion by the mouse OSCC cell line SCCVII. We examined the inhibitory effects of IMD-0560 on NF-κB activity and tumor invasion using human OSCC cell lines and SCCVII cells in vitro. Using a mouse model of jaw bone invasion by SCCVII cells, we assessed the inhibitory effect of IMD-0560 on jaw bone invasion, tumor growth, and matrix degradation in vivo. IMD-0560 suppressed the nuclear translocation of NF-κB and the degradation of IκBα in OSCC cells. IMD-0560 also inhibited invasion by suppressing matrix metalloproteinase-9 (MMP-9) production in OSCC cells. IMD-0560 protected against zygoma and mandible destruction by SCCVII cells, reduced the number of osteoclasts by inhibiting receptor activator of NF-κB ligand (RANKL) expression in osteoblastic cells and SCCVII cells, increased SCCVII cell death and suppressed cell proliferation and MMP-9 production in SCCVII cells. Based on these results, IMD-0560 may represent a new therapeutic agent for bone invasion by OSCC cells.
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan. Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Yukiyo
Y
Tada
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Shoichiro
S
Kokabu
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Goro
G
Sugiyama
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Chihiro
C
Nakatomi
Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kazuhiro
K
Aoki
Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Tamura, Sawara-ku, Fukuoka, Japan.
Hidefumi
H
Fukushima
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka-shi, Saitama, Japan.
Kenji
K
Osawa
Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Yasutaka
Y
Sugamori
Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Keiichi
K
Ohya
Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Shirokane, Minato-ku, Tokyo, Japan.
Masato
M
Okamoto
Institute of Medical Molecular Design Inc (IMMD Inc), Hongo, Bunkyo-ku, Tokyo, Japan.
Tomoyuki
T
Fujikawa
Institute of Medical Molecular Design Inc (IMMD Inc), Hongo, Bunkyo-ku, Tokyo, Japan.
Akiko
A
Itai
Division of Oral Pathology, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Kou
K
Matsuo
Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Seiji
S
Watanabe
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan. Center for Oral Biological Research, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Eijiro
E
Jimi
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000556:secondary*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D060888:Real-Time Polymerase Chain Reaction
D001549:Benzamides; D004791:Enzyme Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide