Browse > Article
http://dx.doi.org/10.4062/biomolther.2014.081

Novel Suppressive Effects of Ketotifen on Migration and Invasion of MDA-MB-231 and HT-1080 Cancer Cells  

Kim, Hyun Ji (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Park, Mi Kyung (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Kim, Soo Youl (National Cancer Center)
Lee, Chang Hoon (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Publication Information
Biomolecules & Therapeutics / v.22, no.6, 2014 , pp. 540-546 More about this Journal
Abstract
The high mortality rates associated with cancer reflect the metastatic spread of tumor cells from the site of their origin. Metastasis, in fact, is the cause of 90% of cancer deaths. Therefore, considerable effort is being made to inhibit metastasis. In the present study, we screened ketotifen for anti-migratory and anti-invasive activities against MDA-MB-231 breast cancer and HT-1080 fibrosarcoma cancer cells. Cancer cell migration and invasion were measured using multi-well chambers. Additionally, western blots were used to examine the effects of ketotifen on the expressions of CDC42, Rho, Rac, and matrix metalloproteinase 9 (MMP-9). The results showed that ketotifen dose-dependently suppressed the migration and invasion of MDA-MB-231 and HT-1080 cells. Ketotifen also suppressed the expressions of CDC42, Rac, and Rho, which, significantly, are involved in MDA-MB-231 and HT-1080 cancer cell migration. Moreover, ketotifen suppressed the expression and activity of MMP-9, which is involved in degradation of the extracellular matrix leading to invasion. The overall data suggested that ketotifen suppresses the migration and invasion of MDA-MB-231 and HT-1080 cancer cells via inhibition of CDC42, Rac, Rho, and MMP-9 expression.
Keywords
Ketotifen; Migration; Invasion; MDA-MB-231; HT-1080;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Aspenstrom, P. (2004) Integration of signalling pathways regulated by small GTPases and calcium. Biochim. Biophys. Acta 1742, 51-58.   DOI
2 Bravo-Cordero, J. J., Hodgson, L. and Condeelis, J. (2012) Directed cell invasion and migration during metastasis. Curr. Opin. Cell Biol. 24, 277-283.   DOI
3 Bray, K., Gillette, M., Young, J., Loughran, E., Hwang, M., Sears, J. C. and Vargo-Gogola, T. (2013) Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration. Breast Cancer Res. 15, R91.   DOI
4 Brinckerhoff, C. E. and Matrisian, L. M. (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat.Rev. Mol. Cell Biol. 3, 207-214.   DOI   ScienceOn
5 Cailleau, R., Young, R., Olive, M. and Reeves, W. J., Jr. (1974) Breast tumor cell lines from pleural effusions. J. Natl. Cancer Inst. 53, 661-674.   DOI
6 Cricco, G., Nunez, M., Medina, V., Garbarino, G., Mohamad, N., Gutierrez, A., Cocca, C., Bergoc, R., Rivera, E. and Martin, G. (2006) Histamine modulates cellular events involved in tumour invasiveness in pancreatic carcinoma cells. Inflamm.Res. 55 Suppl 1, S83-84.   DOI
7 Ellenbroek, S. I. and Collard, J. G. (2007) Rho GTPases: functions and association with cancer. Clin. Exp. Metastasis 24, 657-672.   DOI
8 Elliott, R. L. (2012) Four lessons from global health drug discovery: medicine for an ailing industry? ACS Med. Chem. Lett. 3, 688-690.   DOI
9 Ferry, G., Boutin, J. A., Hennig, P., Genton, A., Desmet, C., Fauchere, J. L., Atassi, G. and Tucker, G. C. (1998) A zinc chelator inhibiting gelatinases exerts potent in vitro anti-invasive effects. Eur. J. Pharmacol. 351, 225-233.   DOI
10 Geiser, A. G., Anderson, M. J. and Stanbridge, E. J. (1989) Suppression of tumorigenicity in human cell hybrids derived from cell lines expressing different activated ras oncogenes. Cancer Res. 49, 1572-1577.
11 Friedl, P. and Wolf, K. (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3, 362-374.   DOI   ScienceOn
12 Fritz, G., Brachetti, C., Bahlmann, F., Schmidt, M. and Kaina, B. (2002) Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br.J. Cancer 87, 635-644.   DOI
13 Fritz, G., Just, I. and Kaina, B. (1999) Rho GTPases are over-expressed in human tumors. Int. J.Cancer 81, 682-687.   DOI   ScienceOn
14 Gommerman, J. L. and Berger, S. A. (1998) Protection from apoptosis by steel factor but not interleukin-3 is reversed through blockade of calcium influx. Blood 91, 1891-1900.
15 Grahnen, A., Lonnebo, A., Beck, O., Eckernas, S. A., Dahlstrom, B. and Lindstrom, B. (1992) Pharmacokinetics of ketotifen after oral administration to healthy male subjects. Biopharm. Drug Dispos. 13, 255-262.   DOI   ScienceOn
16 Gschwandtner, M., Purwar, R., Wittmann, M., Baumer, W., Kietzmann, M., Werfel, T. and Gutzmer, R. (2008) Histamine upregulates keratinocyte MMP-9 production via the histamine H1 receptor. J. Invest. Dermatol. 128, 2783-2791.   DOI
17 Gupta, S. C., Sung, B., Prasad, S., Webb, L. J. and Aggarwal, B. B. (2013) Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol. Sci. 34, 508-517.   DOI
18 Jung, K. H., Park, B. H. and Hong, S. S. (2012) Progress in cancer therapy targeting c-Met signaling pathway. Arch. Pharm. Res. 35, 595-604.   DOI
19 Kobayashi, K., Matsumoto, S., Morishima, T., Kawabe, T. and Okamoto, T. (2000) Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 60, 3978-3984.
20 Kim, H. R., Kim, J. M., Kim, M. S., Hwang, J. K., Park, Y. J., Yang, S. H., Kim, H. J., Ryu, D. G., Lee, D. S., Oh, H., Kim, Y. C., Rhee, Y. J., Moon, B. S., Yun, J. M., Kwon, K. B. and Lee, Y. R. (2014) Saussurea lappa extract suppresses TPA-induced cell invasion via inhibition of NF-kappaB-dependent MMP-9 expression in MCF-7 breast cancer cells. BMC Complement. Altern. Med. 14, 170.   DOI
21 Mazzocca, A. and Carloni, V. (2009) The metastatic process: methodological advances and pharmacological challenges. Curr. Med. Chem. 16, 1704-1717.   DOI
22 Meng, F., Han, Y., Staloch, D., Francis, T., Stokes, A. and Francis, H. (2011) The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. Hepatology 54, 1718-1728.   DOI
23 Medina, V., Croci, M., Crescenti, E., Mohamad, N., Sanchez-Jimenez, F., Massari, N., Nunez, M., Cricco, G., Martin, G., Bergoc, R. and Rivera, E. (2008) The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol. Ther. 7, 28-35.   DOI
24 Medina, V. A. and Rivera, E. S. (2010) Histamine receptors and cancer pharmacology. Br. J. Pharmacol. 161, 755-767.   DOI   ScienceOn
25 Mendoza, M. and Khanna, C. (2009) Revisiting the seed and soil in cancer metastasis. Int. J. Biochem. Cell Biol. 41, 1452-1462.   DOI   ScienceOn
26 Pacharn, P. and Vichyanond, P. (2013) Immunomodulators for conjunctivitis. Curr. Opin. Allergy Clin. Immunol. 13, 550-557.   DOI
27 Rasheed, S., Nelson-Rees, W. A., Toth, E. M., Arnstein, P. and Gardner, M. B. (1974) Characterization of a newly derived human sarcoma cell line (HT-1080). Cancer 33, 1027-1033.   DOI
28 Park, M. K., Jo, S. H., Lee, H. J., Kang, J. H., Kim, Y. R., Kim, H. J., Lee, E. J., Koh, J. Y., Ahn, K. O., Jung, K. C., Oh, S. H., Kim, S. Y. and Lee, C. H. (2013) Novel suppressive effects of cardamonin on the activity and expression of transglutaminase-2 lead to blocking the migration and invasion of cancer cells. Life Sci. 92, 154-160.   DOI   ScienceOn
29 Park, M. K. and Lee, C. H. (2011) Alpinia katsumadai suppresses migration and 12-O-tetradecanoylphorbol-13-acetate-induced invasion of HT-1080 cells through suppression of transglutaminase-2, matrix metalloproteinase-2, and matrix metalloproteinase-9 expression. Cancer Prev. Res. 16, 326-332.
30 Parri, M. and Chiarugi, P. (2010) Rac and Rho GTPases in cancer cell motility control. Cell Commun. Signal. 8, 23.   DOI   ScienceOn
31 Schwarzer, G., Bassler, D., Mitra, A., Ducharme, F. M. and Forster, J. (2004) Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. Cochrane Database Syst. Rev. CD001384.
32 Soboloff, J. and Berger, S. A. (2002) Sustained ER Ca2+ depletion suppresses protein synthesis and induces activation-enhanced cell death in mast cells. J. Biol. Chem. 277, 13812-13820.   DOI
33 Soboloff, J., Zhang, Y., Minden, M. and Berger, S. A. (2002) Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging. Exp. Hematol. 30, 1219-1226.   DOI   ScienceOn
34 Valastyan, S. and Weinberg, R. A. (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292.   DOI   ScienceOn
35 Zhang, Y., Crump, M. and Berge, S. A. (2002) Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death. Breast Cancer Res. Treat. 72, 265-278.   DOI
36 Xu, D., McKee, C. M., Cao, Y., Ding, Y., Kessler, B. M. and Muschel, R. J. (2010) Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. Cancer Res. 70, 6988-6998.   DOI
37 Zamboni, W. C., Torchilin, V., Patri, A. K., Hrkach, J., Stern, S., Lee, R., Nel, A., Panaro, N. J. and Grodzinski, P. (2012) Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin. Cancer Res. 18, 3229-3241.   DOI
38 Zhang, Y. and Berger, S. A. (2003) Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo. Cancer Chemother. Pharmacol. 51, 407-414.
39 Moore, D. H., Allison, B., Look, K. Y., Sutton, G. P. and Bigsby, R. M. (1997) Collagenase expression in ovarian cancer cell lines. Gynecol. Oncol. 65, 78-82.   DOI
40 Franzius, D., Hoth, M. and Penner, R. (1994) Non-specific effects of calcium entry antagonists in mast cells. Pflugers Arch. 428, 433-438.   DOI