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http://dx.doi.org/10.4062/biomolther.2018.091

Discovery of an Indirubin Derivative as a Novel c-Met Kinase Inhibitor with In Vitro Anti-Tumor Effects  

Ndolo, Karyn Muzinga (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
An, Su Jin (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
Park, Kyeong Ryang (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
Lee, Hyo Jeong (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
Yoon, Kyoung Bin (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
Kim, Yong-Chul (School of Life Sciences, Gwangju Institute of Science & Technology)
Han, Sun-Young (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
Publication Information
Biomolecules & Therapeutics / v.27, no.2, 2019 , pp. 216-221 More about this Journal
Abstract
The c-Met protein is a receptor tyrosine kinase involved in cell growth, proliferation, survival, and angiogenesis of several human tumors. Overexpression of c-Met has been found in gastric cancers and correlated with a poor prognosis. Indirubin is the active component of Danggui Longhui Wan, which is a traditional Chinese antileukemic recipe. In the present study, we tested the anti-cancer effects of an indirubin derivative, LDD-1937, on human gastric cancer cells SNU-638. When we performed the in vitro kinase assay against the c-Met activity, LDD-1937 inhibited the activity of c-Met. This result was confirmed by immunoblot and immunofluorescence of phosphorylated c-Met. Immunoblot analysis showed that LDD-1937 decreased the expression of the Erk1/2, STAT3, STAT5, and Akt, downstream proteins of c-Met. In addition, LDD-1937 reduced the cell viability and suppressed colony formation and migration of SNU-638 cells. Furthermore, LDD-1937 induced $G_2/M$ phase arrest in the SNU-638 cells by decreasing the expression levels of cyclin B1 and CDC2. Cleaved-PARP, an apoptosis-related protein, was up-regulated in cells treated with LDD-1937. Overall, this study suggests that LDD-1937 may be a novel small-molecule with therapeutic potential for selectively inhibiting c-Met and c-Met downstream pathways in human gastric cancers overexpressing c-Met.
Keywords
Gastric cancer; Indirubin; c-Met; LDD-1937;
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1 Chen, H., Huang, Q., Dong, J., Wang, A. D. and Lan Q. (2008) Overexpression of CDC2/cyclin B1 in gliomas, and CDC2 depletion inhibits proliferation of human glioma cells in vitro and in vivo. BMC Cancer 8, 29-40.   DOI
2 Choi, S. J., Moon, M. J., Lee, S. D., Choi, S. U., Han, S. Y. and Kim, Y. C. (2010) Indirubin derivatives as a potent FLT3 inhibitors with antiproliferative activity of acute myeloid leukemic cells. Bioorg. Med. Chem. Lett. 20, 2033-2040.   DOI
3 Christensen, J. G., Burrows, J. and Salgia, R. (2005) c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225, 1-26.   DOI
4 Ervik, M., Lam, F., Ferlay J., Mery, L., Soerjomataram, I. and Bray, F. (2016) Cancer Today. International Agency for Research on Cancer, Lyon, France. Available from: http://gco.iarc.fr/today/.
5 Hoessel, R., Leclerc, S., Endicott, J. A., Nobel, M. E., Lawrie, A., Tunnah, P., Leost, M., Damiens, E., Marie, D., Marko, D., Niederberger, E., Tang, W., Eisenbrand, G. and Meijer, L. (1999) Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat. Cell Biol. 1, 60-67.   DOI
6 Kang, Y. K., Muro, K., Ryu, M. H., Yasui, H., Nishina, T., Ryoo, B. Y., Kamiya, Y., Akinaga, S. and Boku, N. (2014) A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer. Invest. New Drug 32, 355-361.   DOI
7 Lee, D. H., Sung, E. S., Ahn, J. H., Huh, J. W. and You, W. K. (2015a) Development of antibody-based c-Met inhibitors for targeted cancer therapy. Immunotargets Ther. 4, 35-44.
8 Lee, H. J., Lee, J., Jeong, P., Choi, J., Baek, J., Ahn, S. J., Moon, Y., Heo, J. D., Choi, Y. H., Chin, Y. W., Kim, Y. C. and Han, S. Y. (2018) Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia. Oncotarget 9, 924-936.   DOI
9 Lemmon, M. A. and Schlessinger, J. (2010) Cell signaling by receptortyrosine kinases. Cell 141, 1117-1134.   DOI
10 Liu, X., Newton, R. C. and Scherle, P. A. (2010) Developing c-Met pathway inhibitors for cancer therapy: progress and challenges. Trends Mol. Med. 16, 37-45.   DOI
11 Ma, P. C., Maulik, G., Christensen, J. and Salgia, R. (2003) c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metast. Rev. 22, 309-325.   DOI
12 Moon, M. J., Lee, S. K., Lee, J. W., Song, W. K., Kim, S. W., Kim, J. I., Cho, C. H., Choi, S. J. and Kim, Y. C. (2006) Synthesis and structure-activity relationships of novel indirubin derivatives as potent anti-proliferative agents with CDK2 inhibitory activities. Bioorg. Med. Chem. 14, 237-246.   DOI
13 Mughal, A., Aslam, H. M., Sheikh, A. and Khan, A. M. H. (2013) c-Met inhibitors. Infect. Agent. Cancer 8, 13.   DOI
14 Nam, S. K., Scuto, A., Yang, F., Chen, W. Y., Park, S. M., Yoo, H. S., Koning, H., Bhatia, R., Cheng, X., Merz, K. H., Eisenbrand, G. and Jove, R. (2012) Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol. Oncol. 6, 276-283.   DOI
15 Puri, N., Khramtsov, A., Ahmed, S., Nallasura, V., Hetzel, J. T., Jagadeeswaran, R., Karczman, G. and Salgia, R. (2007) A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 67, 3529-3534.   DOI
16 Que, W. and Chen, J. (2011) Knockdown of c-Met inhibits cell proliferation and invasion and increaseds chemosensitivity to doxorubicin in human multiple myeloma U266 cells in vitro. Mol. Med. Rep. 4, 343-349.   DOI
17 Lee, J. J. X., Chan, J. J. and Choo, S. P. (2015b) Clinical development of c-MET inhibition in hepatocellular carcinoma. Diseases 3, 306-324.   DOI
18 Rodrigues, G. A. and Park, M. (1994) Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene 9, 2019-2027.
19 Sawyers, C. (2004) Targeted cancer therapy. Nature 432, 294-297.   DOI
20 Smits, V. A. and Medema, R. H. (2001) Checking out the G(2)/M transition. Biochim. Biophys. Acta 1519, 1-12.   DOI
21 You, W. K. and McDonald, D. M. (2008) The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep. 41, 833-839.   DOI
22 Wilson, L. J., Linley, A., Hammond, D. E., Hood, F. E., Coulson, J. M., MacEwan, D. J., Ross, S. J., Slupsky, J. R., Smith, P. D., Eyers, P. A. and Prior, I. A. (2018) New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Res. 78, 15-29.   DOI
23 Zhu, K., Kong, X., Zhao, D., Liang, Z. and Luo, C. (2014) c-Met kinase inhibitors: a patent review (2011-2013). Expert Opin. Ther. Pat. 24, 217-230.   DOI
24 Annual report of cancer statistics in Korea in 2015 (2017) Korea Central Cancer Registry. Available from: http://www.cancer.go.kr/.
25 Blazevic, T., Heiss, E. H., Atanasov, A. G., Breuss, J. M., Dirsch, V. M. and Uhrin, P. (2015) Indirubin and indirubin derivatives for counteracting proliferative disease. Evid. Based Complement. Alternat. Med. 2015, 654098-654110.
26 Bradley, C. A., Salto-Tellez, M., Laurent-Puig, P., Bardelli, A., Rolfo, C., Tabernero, J, Khawaja, H. A., Lawler, M., Johnston, P. G. and Van Schaeybroeck, S. (2017) Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat. Rev. Clin. Oncol. 14, 562-576.   DOI
27 Chan, A. O. O. and Wong, B. (2015) Epidemiology of Gastric Cancer (M. F. Post, Ed.). Uptodate. Available from: http://www.uptodate.com/contents/epidemiology-of-gastric-cancer/.