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Inhibitory Effects of Clotrimazole on TNF-α-induced Adhesion Molecule Expression and Angiogenesis
Dinesh Thapa,이종숙,Min-A Park,Mi-Yeon Cho,최한곤,Tae Cheon Jeong,김정애,박영준 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.4
Cell adhesion molecules play a pivotal role in chronic inflammation and pathological angiogenesis. In the present study, we investigated the inhibitory effects of clotrimazole (CLT) on tumor necrosis factor (TNF)-α-induced changes in adhesion molecule expression. CLT dosedependently inhibited monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expressions in TNF-α-stimulated HT29 colonic epithelial cells. This inhibitory action of CLT correlated with a significant reduction in TNF-α-induced adhesion of monocytes to HT29 cells, which was comparable to the inhibitory effects of anti-ICAM-1 and VCAM-1 monoclonal antibodies on monocyte-epithelial adhesion. These inhibitory actions of CLT were, at least in part, attributable to the inhibition of redox sensitive NF-κB activation, as CLT inhibited TNF-α-induced ROS generation as well as NF-κB nuclear translocation and activation in HT29 cells. Furthermore, the inhibition of TNF-α-induced monocyte adhesion was also mimicked by the specific NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). Inflammatory mediators including TNF-α have known to promote angiogenesis, which in turn further contributes to inflammatory pathology. Therefore, we additionally evaluated whether CLT modulates TNF-α-induced angiogenesis using in vivo chick chorioallantoic membrane (CAM) assay. The CAM assay showed that CLT dose-dependently attenuated TNF-α-induced angiogenesis, and the effect was correlated with decreased inflammation of the CAM tissue. In conclusion, our results suggest that CLT can inhibit TNF-α-triggered expression of adhesion molecules, ICAM-1 and VCAM-1, and angiogenesis during inflammation.
Dinesh Babu,박수영,김영휘,양홍철,김정애,Dinesh Thapa,이종숙,김아라 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.1
An aqueous extract of Cornus kousa Burg. leaves (ACK) that contained high amount of polyphenols showed significant antioxidant activity against diphenylpicrylhydrazyl (DPPH) radicals and TNF-α-generated reactive oxygen species. ACK at concentrations of 10 and 50 μg/mL significantly inhibited TNF- α-induced adhesion of U937 pre-monocytic cells to HT-29 colon epithelial cells in a concentrationdependent manner. The reduced adhesion by ACK correlated with the suppressed expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8, the major inflammatory bowel disease (IBD)-associated chemokines. Moreover, ACK significantly suppressed TNF-α-induced translocation of redox-sensitive nuclear factor (NF)-κB as well as degradation of cytosolic I-κBα. The effective concentrations of ACK were much lower than that of 5-aminosalicylic acid (3.06 mg/mL), which is an active metabolite of sulfasalazine, a well-known drug used in the treatment of IBD. The results indicate that ACK may provide a potential benefit for the prevention and treatment of inflammatory diseases such as IBD.
( Dinesh Thapa ),( Youra Kang ),( Pil Hoon Park ),( Seok Kyun Noh ),( Yong Rok Lee ),( Sung Soo Han ),( Sae Kwang Ku ),( Yun Jin Jung ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, anovel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl(2)), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E(2) (PGE(2)) concentrations in CoCl(2)-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl(2) did not alter the basal expression of VEGF and COX-2, or PGE(2) production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl(2)-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as ananti-tumor agent with a HIF-1α inhibitory activity.