Abstract
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 dose-dependently 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.
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Babu, D., Lee, J. S., Park, S. Y., Thapa, D., Choi, M. K., Kim, A. R., Park, Y. J., and Kim, J.-A., Involvement of NF-kappaB in the inhibitory actions of Platycarya strobilacea on the TNF-alpha-induced monocyte adhesion to colon epithelial cells and chemokine expression. Arch. Pharm. Res., 31, 727–735 (2008).
Banks, C., Bateman, A., Payne, R., Johnson, P., and Sheron, N., Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn’s disease. J. Pathol., 199, 28–35 (2003).
Belo, A. V., Barcelos, L. S., Teixeira, M. M., Ferreira, M. A., and Andrade, S. P., Differential effects of antiangiogenic compounds in neovascularization, leukocyte recruitment, VEGF production, and tumor growth in mice. Cancer Invest., 22, 723–729 (2004).
Bendjelloul, F., Malý, P., Mandys, V., Jirkovská, M., Prokesová, L., Tucková, L., and Tlaskalová-Hogenová, H., Intercellular adhesion molecule-1 (ICAM-1) deficiency protects mice against severe forms of experimentally induced colitis. Clin. Exp. Immunol., 119, 57–63 (2000).
Benzaquen, L. R., Brugnara, C., Byers, H. R., Gatton-Celli, S., and Halperin, J. A., Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat. Med., 1, 534–540 (1995).
Bian, X. W., Chen, J. H., Jiang, X. F., Bai, J. S., Wang, Q. L., and Zhang, X., Angiogenesis as an immunopharmacologic target in inflammation and cancer. Int. Immunopharmacol., 4, 1537–1547 (2004).
Carmeliet, P. and Jain, R. K., Angiogenesis in cancer and other diseases. Nature, 407, 249–257 (2000).
Chidlow, J. H. Jr., Shukla, D., Grisham, M. B., and Kevil, C. G., Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am. J. Physiol. Gastrointest. Liver Physiol., 293, G5–G18 (2007).
Costa, C., Incio, J., and Soares, R., Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis, 10, 149–166 (2007).
Dianzani, C., Brucato, L., Gallicchio, M., Rosa, A. C., Collino, M., and Fantozzi, R., Celecoxib modulates adhesion of HT29 colon cancer cells to vascular endothelial cells by inhibiting ICAM-1 and VCAM-1 expression. Br. J. Pharmacol., 153, 1153–1561 (2008).
Dippold, W., Wittig, B., Schwaeble, W., Mayet, W., and Meyer zum Buschenfelde, K. H., Expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in colonic epithelial cells. Gut, 34, 1593–1597 (1993).
Gallicchio, M., Rosa, A. C., Dianzani, C., Brucato, L., Benetti, E., Collino, M., and Fantozzi, R., Celecoxib decreases expression of the adhesion molecules ICAM-1 and VCAM-1 in a colon cancer cell line (HT29). Br. J. Pharmacol., 153, 870–878 (2008).
Glass, C. K. and Witztum, J. L., Atherosclerosis: the road ahead. Cell, 104, 503–516 (2001).
Göke, M., Hoffmann, J. C., Evers, J., Krüger, H., and Manns, M. P., Elevated serum concentrations of soluble selectin and immunoglobulin type adhesion molecules in patients wih inflammatory bowel disease. J. Gastroenterol., 32, 480–486 (1997).
Grgic, I., Eichler, I., Heinau, P., Si, H., Brakemeier, S., Hoyer, J., and Köhler, R., Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler. Thromb. Vasc. Biol., 25, 704–709 (2005).
Hauser, I. A., Johnson, D. R., and Madri, J. A., Differential induction of VCAM-1 on human iliac venous and arterial endothelial cells and its role in adhesion. J Immunol., 151, 5172–5185 (1993).
Jackson, J. R., Seed, M. P., Kircher, C. H., Willoughby, D. A., and Winkler, J. D., The codependence of angiogenesis and chronic inflammation. FASEB J., 11, 457–465 (1997).
Jobin, C., Hellerbrand, C., Licato, L.L., Brenner, D. A., and Sartor, R. B., Mediation by NF-kappa B of cytokine induced expression of intercellular adhesion molecule 1 (ICAM-1) in an intestinal epithelial cell line, a process blocked by proteasome inhibitors. Gut, 42, 779–787 (1998).
Jones, S. C., Banks, R. E., Haidar, A., Gearing, A. J., Hemingway, I. K., Ibbotson, S. H., Dixon, M. F., and Axon, A. T., Adhesion molecules in inflammatory bowel disease. Gut, 36, 724–730 (1995).
Kawachi, S., Cockrell, A., Laroux, F. S., Gray, L., Granger, D. N., van der Heyde, H. C., and Grisham, M. B., Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation. Am. J. Physiol. Gastrointest. Liver Physiol., 277, G572–G576 (1999).
Khalid, M. H., Tokunaga, Y., Caputy, A. J., and Walters, E., Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole. J. Neurosurg., 103, 79–86 (2005).
Kobayashi, H., Boelte, K. C., and Lin, P. C., Endothelial cell adhesion molecules and cancer progression. Curr. Med. Chem., 14, 377–386 (2007).
Kopp, E. and Ghosh, S., Inhibition of NF-kappa B by sodium salicylate and aspirin. Science, 265, 956–959 (1994).
Koutroubakis, I. E., Tsiolakidou, G., Karmiris, K., and Kouroumalis, E. A., Role of angiogenesis in inflammatory bowel disease. Inflamm. Bowel Dis., 12, 515–523 (2006).
Krieglstein, C. F., Salter, J. W., Cerwinka, W. H., Russell, J. M., Schuermann, G., Bruewer, M., Laroux, F. S., Grisham, M. B., and Granger, D. N., Role of intercellular adhesion molecule 1 in indomethacin-induced ileitis. Biochem. Biophys. Res. Commun., 282, 635–642 (2001).
Langston, W., Chidlow, J. H. Jr., Booth, B. A., Barlow, S. C., Lefer, D. J., Patel, R. P., and Kevil, C. G., Regulation of endothelial glutathione by ICAM-1 governs VEGF-Amediated eNOS activity and angiogenesis. Free Radic. Biol. Med., 42, 720–729 (2007).
Lazzarino, D. A., de Diego, M., Hirschman, S. Z., Zhang, K. Y., Shaikh, S., Musi, E., Liaw, L., and Alexander, R. J., IL-8 and MCP-1 secretion is enhanced by the peptide-nucleic acid immunomodulator, Product R, in U937 cells and primary human monocytes. Cytokine, 14, 234–239 (2001).
Logsdon, N. J., Kang, J., Togo, J. A., Christian, E. P., and Aiyar, J., A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. J. Biol. Chem., 272, 32723–32726 (1997).
Park, B. C., Park, S. Y., Lee, J. S., Mousa, S. A., Kim, J. T., Kwak, M. K., Kang, K. W., Lee, E. S., Choi, H. G., Yong, C. S., and Kim, J.-A., The anti-angiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone are mediated through the suppression of both VEGF production and VEGF-induced signaling. Vascul. Pharmacol., 50, 123–131 (2009).
Pierce, J. W., Read, M. A., Ding, H., Luscinskas, F. W., and Collins, T., Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J. Immunol., 156, 3961–3969 (1996).
Pousa, I. D., Maté, J., and Gisbert, J. P., Angiogenesis in inflammatory bowel disease. Eur. J. Clin. Invest., 38, 73–81 (2008).
Read, M. A., Neish, A. S., Luscinskas, F. W., Palombella V. J., Maniatis, T., and Collins, T., The proteasome pathway is required for cytokine-induced endothelialleukocyte adhesion molecule expression. Immunity, 2, 493–506 (1995).
Rijcken, E., Krieglstein, C. F., Anthoni, C., Laukoetter, M. G., Mennigen, R., Spiegel, H. U., Senninger, N., Bennett, C. F., and Schuermann, G., ICAM-1 and VCAM-1 antisense oligonucleotides attenuate in vivo leucocyte adherenceand inflammation in rat inflammatory bowel disease. Gut, 51, 529–535 (2002).
Rivera-Nieves, J., Gorfu, G., and Ley, K., Leukocyte adhesion molecules in animal models of inflammatory bowel disease. Inflamm. Bowel. Dis., 14, 1715–1735 (2008).
Sans, M., Panés, J., Ardite, E., Elizalde, J. I., Arce, Y., Elena, M., Palacín, A., Fernández-Checa, J. C., Anderson, D. C., Lobb, R., and Piqué, J. M., VCAM-1 and ICAM-1 mediate leukocyte-endothelial cell adhesion in rat experimental colitis. Gastroenterology, 116, 874–883 (1999).
Schmidmaier, R. and Baumann, P., ANTI-ADHESION evolves to a promising therapeutic concept in oncology. Curr. Med. Chem., 15, 978–990 (2008).
Sun, F. F., Lai, P. S., Yue, G., Yin, K., Nagele, R. G., Tong, D. M., Krzesicki, R. F., Chin, J. E., and Wong, P. Y., Pattern of cytokine and adhesion molecule mRNA in hapten-induced relapsing colon inflammation in the rat. Inflammation, 25, 33–45 (2001).
Tak, P. P. and Firestein, G. S., NF-κB: a key role in inflammatory disease. J. Clin. Invest., 107, 7–11 (2001).
Takahashi, H., Abe, M., Sugawara, T., Tanaka, K., Saito, Y., Fujimura, S., Shibuya, M., and Sato, Y., Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis. Jpn. J. Cancer Res., 89, 445–451 (1998).
Thapa, D., Kwon, J. B., and Kim, J.-A., Role of intracellular calcium in clotrimazole-induced alteration of cell cycle inhibitors, p53 and p27, in HT29 human colon adenocarcinoma cells. Biomolecules & Therapeutics, 16, 21–27 (2008a).
Thapa, D., Lee, J. S., Park, S. Y., Bae, Y. H., Bae, S. K., Kwon, J. B., Kim, K. J., Kwak, M. K., Park, Y. J., Choi, H. G., and Kim, J.-A., Clotrimazole ameliorates intestinal inflammation and abnormal angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-kappaB-dependent manner. J. Pharmacol. Exp. Ther., 327, 353–364 (2008b).
Yusuf-Makagiansar, H., Anderson, M. E., Yakovleva, T. V., Murray, J. S., Siahaan, T. J., Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med. Res. Rev., 22, 146–167 (2002).
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Thapa, D., Lee, J.S., Park, MA. et al. Inhibitory effects of clotrimazole on TNF-α-induced adhesion molecule expression and angiogenesis. Arch. Pharm. Res. 32, 593–603 (2009). https://doi.org/10.1007/s12272-009-1416-6
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DOI: https://doi.org/10.1007/s12272-009-1416-6