n-(2-5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide and Disease-Models--Animal

The transcriptional factor nuclear factor κB(NF-κB)regulates the expression of a wide variety of genes that are involved in immune and inflammatory responses, proliferation, and tumorigenesis. NF-κB consists of five members, such as p65(RelA), RelB, c-Rel, p50/p105(NF-κB1), and p52/p100(NF-κB2). There are two distinct NF-κB activation pathways, termed the classical and alternative NF-κB signaling pathways. Since mice lacking both p50 and p52 subunits developed typical osteopetrosis, due to total lack of osteoclasts, NF-κB is also important osteoclast differentiation. A selective NF-κB inhibitor blocked receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis both in vitro and in vivo. Recent findings have shown that inactivation of NF-κB enhances osteoblast differentiation in vitro and bone formation in vivo. NF-κB is constitutively activated in many cancers including oral squamous cell carcinoma(OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-κB inhibitor also prevented jaw bone destruction by OSCC by reduced osteoclast numbers in animal model. Thus the inhibition of NF-κB might useful for the treatment of bone diseases, such as arthritis, osteoporosis, periodontitis, and bone invasion by OSCC by inhibiting bone resorption and by stimulating bone formation.

Topics: Animals; Benzamides; Carcinoma, Squamous Cell; Cell Differentiation; Disease Models, Animal; Humans; Jaw; Jaw Neoplasms; Mice; Neoplasm Invasiveness; NF-kappa B; Osteoblasts; Osteoclasts; Osteogenesis; RANK Ligand; Signal Transduction

Preterm delivery (PTD) remains a serious challenge in perinatology. Intrauterine infection and/or inflammation, followed by increased inflammatory cytokines, represented by IL-6, are involved in this pathology. Our aim was to identify IL-6-producing cells in the placenta and to analyze the potential of targeting IκB kinase β (IKKβ) signaling to suppress IL-6 production for the treatment of PTD. Immunohistochemical analyses using placentas complicated with severe chorioamnionitis revealed that IL-6 is mainly expressed in human amniotic mesenchymal stromal cells (hAMSCs). Primary hAMSCs were collected, and strong IL-6 expression was confirmed. In hAMSCs, the treatment of tumor necrosis factor-α or IL-1β drastically induced IL-6 production, followed by the phosphorylation of IKKs. A novel IKKβ inhibitor, IMD-0560, almost completely inhibited IL-6 production from hAMSCs. Using an experimental lipopolysaccharide-induced PTD mouse model, the therapeutic potential of IMD-0560 was examined. IMD-0560 was delivered vaginally 4 hours before lipopolysaccharide administration. Mice in the IMD-0560 (30 mg/kg, twice a day) group had a significantly lower rate of PTD [10 of 22 (45%)] without any apparent adverse events on the mice and their pups. In uteri collected from mice, IMD-0560 inhibited not only IL-6 production but also production of related cytokines, such as keratinocyte-derived protein chemokine/CXCL1, macrophage inflammatory protein-2/CXCL2, and monocyte chemoattractant protein-1/chemokine ligand 2. Targeting IKKβ signaling shows promising effects through the suppression of these cytokines and can be explored as a future option for the prevention of PTD.

Topics: Amnion; Animals; Benzamides; Chorioamnionitis; Disease Models, Animal; Female; Humans; I-kappa B Kinase; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred C3H; Placenta; Pregnancy; Premature Birth

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.

Topics: Animals; Benzamides; Blotting, Western; Bone Neoplasms; Carcinoma, Squamous Cell; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Humans; I-kappa B Proteins; Male; Mice; Microscopy, Fluorescence; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Real-Time Polymerase Chain Reaction

The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis.. We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice.. IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice.. Based on these results, IMD-0560 could be a new therapeutic agent for RA.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Benzamides; Cell Line; Cytokines; Disease Models, Animal; Fibroblasts; Humans; I-kappa B Proteins; In Vitro Techniques; Kidney; Male; Mice; Mice, Inbred DBA; NF-kappa B; Phosphorylation; Synovial Membrane