Oncotarget

Research Papers:

The novel IκB kinase β inhibitor IMD-0560 prevents bone invasion by oral squamous cell carcinoma

Yukiyo Tada, Shoichiro Kokabu, Goro Sugiyama, Chihiro Nakatomi, Kazuhiro Aoki, Hidefumi Fukushima, Kenji Osawa, Yasutaka Sugamori, Keiichi Ohya, Masato Okamoto, Tomoyuki Fujikawa, Akiko Itai, Kou Matsuo, Seiji Watanabe and Eijiro Jimi _

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Oncotarget. 2014; 5:12317-12330. https://doi.org/10.18632/oncotarget.2640

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Abstract

Yukiyo Tada1,2, Shoichiro Kokabu1, Goro Sugiyama1, Chihiro Nakatomi1, Kazuhiro Aoki3, Hidefumi Fukushima4, Kenji Osawa5, Yasutaka Sugamori3, Keiichi Ohya3, Masato Okamoto6, Tomoyuki Fujikawa7, Akiko Itai7, Kou Matsuo8, Seiji Watanabe2 and Eijiro Jimi1,9

1 Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan

2 Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan

3 Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan

4 Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Tamura, Sawara-ku, Fukuoka, Japan

5 Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka-shi, Saitama, Japan

6 Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Shirokane, Minato-ku, Tokyo, Japan

7 Institute of Medical Molecular Design Inc (IMMD Inc), Hongo, Bunkyo-ku, Tokyo, Japan

8 Division of Oral Pathology, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan

9 Center for Oral Biological Research, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan

Correspondence:

Eijiro Jimi, email:

Keywords: NF-κB, IMD-0560, bone invasion, oral squamous cell carcinoma

Received: September 16, 2014 Accepted: October 28, 2014 Published: October 28, 2014

Abstract

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.


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