Tada Yukiyo, Kokabu Shoichiro, Sugiyama Goro, Nakatomi Chihiro, Aoki Kazuhiro, Fukushima Hidefumi, Osawa Kenji, Sugamori Yasutaka, Ohya Keiichi, Okamoto Masato, Fujikawa Tomoyuki, Itai Akiko, Matsuo Kou, Watanabe Seiji, Jimi Eijiro
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.
Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Oncotarget. 2014 Dec 15;5(23):12317-30. doi: 10.18632/oncotarget.2640.
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.
口腔鳞状细胞癌（OSCC）细胞显示出显著增强的核因子κB（NF-κB）活性，抑制这种活性可抑制恶性肿瘤特征。因此，我们评估了IMD-0560（一种新型IκB激酶（IKK）β抑制剂，正在类风湿性关节炎的临床试验中进行评估）对小鼠OSCC细胞系SCCVII骨侵袭的影响。我们在体外使用人OSCC细胞系和SCCVII细胞研究了IMD-0560对NF-κB活性和肿瘤侵袭的抑制作用。使用SCCVII细胞颌骨侵袭的小鼠模型，我们在体内评估了IMD-0560对颌骨侵袭、肿瘤生长和基质降解的抑制作用。IMD-0560抑制了OSCC细胞中NF-κB的核转位和IκBα的降解。IMD-0560还通过抑制OSCC细胞中基质金属蛋白酶-9（MMP-9）的产生来抑制侵袭。IMD-0560可防止SCCVII细胞破坏颧骨和下颌骨，通过抑制成骨细胞和SCCVII细胞中核因子κB受体活化因子配体（RANKL）的表达来减少破骨细胞数量，增加SCCVII细胞死亡，并抑制SCCVII细胞的增殖和MMP-9的产生。基于这些结果，IMD-0560可能代表一种用于治疗OSCC细胞骨侵袭的新型治疗药物。
