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

  • Oncotarget. 2014 Dec 15;5(23):12317-30. doi: 10.18632/oncotarget.2640.
Yukiyo Tada  1 ,  Shoichiro Kokabu  2 ,  Goro Sugiyama  2 ,  Chihiro Nakatomi  2 ,  Kazuhiro Aoki  3 ,  Hidefumi Fukushima  4 ,  Kenji Osawa  5 ,  Yasutaka Sugamori  3 ,  Keiichi Ohya  3 ,  Masato Okamoto  6 ,  Tomoyuki Fujikawa  7 ,  Akiko Itai  7 ,  Kou Matsuo  8 ,  Seiji Watanabe  9 ,  Eijiro Jimi  10
Affiliations
  • 1. 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.
  • 2. Division of Molecular Signaling and Biochemistry, Department of Health Promotion, 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. Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
  • 10. 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.
PMID: 25373602 DOI: 10.18632/oncotarget.2640
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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