Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.200

SP-8356, a (1S)-(-)-Verbenone Derivative, Inhibits the Growth and Motility of Liver Cancer Cells by Regulating NF-κB and ERK Signaling  

Kim, Dong Hwi (Department of Biomedical Science, Korea University College of Medicine)
Yong, Hyo Jeong (Department of Biomedical Science, Korea University College of Medicine)
Mander, Sunam (Department of Biomedical Science, Korea University College of Medicine)
Nguyen, Huong Thi (Department of Biomedical Science, Korea University College of Medicine)
Nguyen, Lan Phuong (Department of Biomedical Science, Korea University College of Medicine)
Park, Hee-Kyung (Department of Biomedical Science, Korea University College of Medicine)
Cha, Hyo Kyeong (Department of Biomedical Science, Korea University College of Medicine)
Kim, Won-Ki (Department of Biomedical Science, Korea University College of Medicine)
Hwang, Jong-Ik (Department of Biomedical Science, Korea University College of Medicine)
Publication Information
Biomolecules & Therapeutics / v.29, no.3, 2021 , pp. 331-341 More about this Journal
Abstract
Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.
Keywords
SP-8356; Liver cancer; Proliferation; Motility; ERK; $NF-{\kappa}B$;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Arii, S., Mise, M., Harada, T., Furutani, M., Ishigami, S., Niwano, M., Mizumoto, M., Fukumoto, M. and Imamura, M. (1996) Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 24, 316-322.   DOI
2 Bruix, J. and Sherman, M.; American Association for the Study of Liver Diseases (2011) Management of hepatocellular carcinoma: an update. Hepatology 53, 1020-1022.   DOI
3 Chaffer, C. L. and Weinberg, R. A. (2011) A perspective on cancer cell metastasis. Science 331, 1559.   DOI
4 Chambard, J. C., Lefloch, R., Pouyssegur, J. and Lenormand, P. (2007) ERK implication in cell cycle regulation. Biochim. Biophys. Acta 1773, 1299-1310.   DOI
5 Chan, C. F., Yau, T. O., Jin, D. Y., Wong, C. M., Fan, S. T. and Ng, I. O. (2004) Evaluation of nuclear factor-kappaB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma. Clin. Cancer Res. 10, 4140-4149.   DOI
6 Chen, L., Li, M., Li, Q., Wang, C. J. and Xie, S. Q. (2013) DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway. Mol. Cancer 12, 157.   DOI
7 Choi, I. Y., Lim, J. H., Hwang, S., Lee, J. C., Cho, G. S. and Kim, W. K. (2010) Anti-ischemic and anti-inflammatory activity of (S)-cisverbenol. Free. Radic. Res. 44, 541-551.   DOI
8 El-Serag, H. B. and Rudolph, K. L. (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557-2576.   DOI
9 Flores, K. and Seger, R. (2013) Stimulated nuclear import by β-like importins. F1000Prime Rep. 5, 41.   DOI
10 Hoesel, B. and Schmid, J. A. (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 12, 86.   DOI
11 Huber, M. A., Azoitei, N., Baumann, B., Grbnert, S., Sommer, A., Pehamberger, H., Kraut, N., Beug, H. and Wirth, T. (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569-581.   DOI
12 Je, Y., Schutz, F. A. B. and Choueiri, T. K. (2009) Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 10, 967-974.   DOI
13 Ju, C., Song, S., Hwang, S., Kim, C., Kim, M., Gu, J., Oh, Y. K., Lee, K., Kwon, J., Lee, K., Kim, W. K. and Choi, Y. (2013) Discovery of novel (1S)-(-)-verbenone derivatives with anti-oxidant and antiischemic effects. Bioorg. Med. Chem. Lett. 23, 5421-5425.   DOI
14 Naugler, W. E. and Karin, M. (2008) NF-κB and cancer-identifying targets and mechanisms. Curr. Opin. Genet. Dev. 18, 19-26.   DOI
15 Min, C., Eddy, S. F., Sherr, D. H. and Sonenshein, G. E. (2008) NF-kappaB and epithelial to mesenchymal transition of cancer. J. Cell. Biochem. 104, 733-744.   DOI
16 Min, L., He, B. and Hui, L. (2011) Mitogen-activated protein kinases in hepatocellular carcinoma development. Semin. Cancer Biol. 21, 10-20.   DOI
17 Nakagawa, H. and Maeda, S. (2012) Inflammation- and stress-related signaling pathways in hepatocarcinogenesis. World J. Gastroenterol. 18, 4071-4081.   DOI
18 Okusaka, T., Okada, S., Ishii, H., Nose, H., Nagahama, H., Nakasuka, H., Ikeda, K. and Yoshimori, M. (1997) Prognosis of hepatocellular carcinoma patients with extrahepatic metastases. Hepatogastroenterology 44, 251-257.
19 Kuo, C. F., Su, J. D., Chiu, C. H., Peng, C. C., Chang, C. H., Sung, T. Y., Huang, S. H., Lee, W. C. and Chyau, C. C. (2011) Anti-inflammatory effects of supercritical carbon dioxide extract and its isolated carnosic acid from Rosmarinus officinalis leaves. J. Agric. Food Chem. 59, 3674-3685.   DOI
20 Coussens, L. M. and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867.   DOI
21 Li, W., Tan, D., Zenali, M. J. and Brown, R. E. (2009) Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma. Int. J. Clin. Exp. Pathol. 3, 238-243.
22 Lin, Y., Liu, J., Huang, Y., Liu, D., Zhang, G. and Kan, H. (2017) microRNA-489 plays an anti-metastatic role in human hepatocellular carcinoma by targeting matrix metalloproteinase-7. Transl. Oncol. 10, 211-220.   DOI
23 Tung-Ping Poon, R., Fan, S. T. and Wong, J. (2000) Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann. Surg. 232, 10-24.   DOI
24 Singh, A. K., Kumar, R. and Pandey, A. K. (2018) Hepatocellular Carcinoma: causes, mechanism of progression and biomarkers. Curr. Chem. Genom. Transl. Med. 12, 9-26.   DOI
25 Wu, J. M., Sheng, H., Saxena, R., Skill, N. J., Bhat-Nakshatri, P., Yu, M., Nakshatri, H. and Maluccio, M. A. (2009) NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. Cancer Lett. 278, 145-155.   DOI
26 Yao, D. F., Wu, X. H., Zhu, Y., Shi, G. S., Dong, Z. Z., Yao, D. B., Wu, W., Qiu, L. W. and Meng, X. Y. (2005) Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int. 4, 220-226.
27 Ola, M. S., Nawaz, M. and Ahsan, H. (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol. Cell. Biochem. 351, 41-58.   DOI
28 Pahk, K., Noh, H., Joung, C., Jang, M., Song, H. Y., Kim, K. W., Han, K., Hwang, J. I., Kim, S. and Kim, W. K. (2019) A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation. J. Transl. Med. 17, 274.   DOI
29 Tong, R., Yang, B., Xiao, H., Peng, C., Hu, W., Weng, X., Cheng, S., Du, C., Lv, Z., Ding, C., Zhou, L., Xie, H., Wu, J. and Zheng, S. (2017) KCTD11 inhibits growth and metastasis of hepatocellular carcinoma through activating Hippo signaling. Oncotarget 8, 37717-37729.   DOI
30 Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J. and Jemal, A. (2015) Global cancer statistics. CA Cancer J. Clin. 2012. 65, 87-108.   DOI
31 Uchino, K., Tateishi, R., Shiina, S., Kanda, M., Masuzaki, R., Kondo, Y., Goto, T., Omata, M., Yoshida, H. and Koike, K. (2011) Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer 117, 4475-4483.   DOI
32 Uka, K., Aikata, H., Takaki, S., Shirakawa, H., Jeong, S. C., Yamashina, K., Hiramatsu, A., Kodama, H., Takahashi, S. and Chayama, K. (2007) Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J. Gastroenterol. 13, 414-420.   DOI
33 Ulisse, S., Baldini, E., Sorrenti, S. and D'armiento, M. (2009) The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr. Cancer Drug Targets 9, 32-71.   DOI
34 Valastyan, S. and Weinberg, R. A. (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-92.   DOI
35 Wang, J., Huang, Q. and Chen, M. (2003) The role of NF-kappaB in hepatocellular carcinoma cell. Chin. Med. J. 116, 747-752.
36 Plotnikov, A., Zehorai, E., Procaccia, S. and Seger, R. (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta 1813, 1619-1633.   DOI
37 Yeh, C. B., Hsieh, M. J., Hsieh, Y. H., Chien, M. H., Chiou, H. L. and Yang, S. F. (2012) Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity. PLoS ONE 7, e31055.   DOI
38 Zhu, Y. J., Zheng, B., Wang, H. Y. and Chen, L. (2017) New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol. Sin. 38, 614-622.   DOI
39 Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and BenNeriah, Y. (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466.   DOI
40 Plotnikov, A., Flores, K., Maik-Rachline, G., Zehorai, E., Kapri-Pardes, E., Berti, D. A., Hanoch, T., Besser, M. J. and Seger, R. (2015) The nuclear translocation of ERK1/2 as an anticancer target. Nat. Commun. 6, 6685.   DOI
41 Poddar, N., Ramlal, R., Ravulapati, S., Devlin, S. M., Gadani, S., Vidal, C. I., Cao, D., Befeler, A. S. and Lai, J. (2017) Extrahepatic metastasis of hepatocellular carcinoma arising from a hepatic adenoma without concurrent intrahepatic recurrence. Curr. Oncol. 24, e333-e336.
42 Ranjan, A., Iyer, S. V., Ward, C., Link, T., Diaz, F. J., Dhar, A., Tawfik, O. W., Weinman, S. A., Azuma, Y., Izumi, T. and Iwakuma, T. (2018) MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma. Oncotarget 9, 21429-21443.   DOI
43 Saharinen, P., Eklund, L., Pulkki, K., Bono, P. and Alitalo, K. (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17, 347-362.   DOI
44 Siegel, R. L., Miller, K. D. and Jemal, A. (2018) Cancer statistics, 2018. CA Cancer J. Clin. 68, 7-30.   DOI
45 Marrero, C. R. and Marrero, J. A. (2007) Viral hepatitis and hepatocellular carcinoma. Arch. Med. Res. 38, 612-620.   DOI
46 Liu, P., Cheng, H., Roberts, T. M. and Zhao, J. J. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627-644.   DOI
47 Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., De Oliveira, A. C., Santoro, A., Raoul, J. L., Forner, A., Schwartz, M., Porta, C., Zeuzem, S., Bolondi, L., Greten, T. F., Galle, P. R., Seitz, J. F., Borbath, I., Haeussinger, D., Giannaris, T., Shan, M., Moscovici, M., Voliotis, D. and Bruix, J. (2008) Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378-390.   DOI
48 Mander, S., Kim, D. H., Thi Nguyen, H., Yong, H. J., Pahk, K., Kim, E. Y., Lee, K., Seong, J. Y., Kim, W. K. and Hwang, J. I. (2019) SP8356, a (1S)-(-)-verbenone derivative, exerts in vitro and in vivo anti-breast cancer effects by inhibiting NF-κB signaling. Sci. Rep. 9, 6595.   DOI