EH-42: A Novel Small Molecule Induces Apoptosis and Inhibits Migration and Invasion of Human Hepatoma Cells through Suppressing STAT3 Signaling Pathway

Author(s): Qi-Zhe Gong, Di Xiao, Gui-Yi Gong, Jian Xu, Xiao-Dong Wen*, Feng Feng*, Wei Qu*

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 7 , 2019

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Graphical Abstract:


Background: Since signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in hepatocellular carcinoma (HCC) and plays a key role in this tumor progression. Inhibition of the STAT3 signaling pathway has been considered as an effective therapeutic strategy for suppressing HCC development.

Objective: In this study, we investigated the anti-cancer effects of EH-42 on HCC cells and tried to explain the underlying mechanism.

Methods: MTT assay, colon formation assay and AnnexinV-FITC/PI double-staining assay were performed to assess the effects of EH-42 on cell growth and survival. Wound healing assay and transwell invasion assay were performed to assess the effects of EH-42 on cell migration and invasion. Western blotting assay was performed to analyze the effects of EH-42 on relative proteins.

Results: According to the MTT assay, colon formation assay and AnnexinV-FITC/PI doublestaining assay, EH-42 could suppress the growth and induce apoptosis of HCC cells in a dosedependent manner. Further western blotting assay showed that the inhibitory effects of EH-42 on cell growth and survival were caused by activating caspase 3/9, suppressing the phospho-STAT3 (Tyr 705) and downregulating anti-apoptotic proteins like Bcl-2/Bcl-xL. Moreover, migration and invasion abilities of HCC cells were also inhibited by EH-42 in the wound healing assay and transwell invasion assay. The potential mechanism was that EH-42 could inhibit HCC metastasis via reversing epithelial-mesenchymal transition and downregulating the secretion of MMPs.

Conclusion: Taken together, these findings suggested that EH-42 could be a potential therapeutic agent for HCC treatment.

Keywords: STAT3, apoptosis, migration, invasion, hepatocellular carcinoma.

Ding, X.X.; Zhu, Q.G.; Zhang, S.M.; Guan, L.; Li, T.; Zhang, L.; Wang, S.Y.; Ren, W.L.; Chen, X.M.; Zhao, J.; Lin, S.; Liu, Z.Z.; Bai, Y.X.; He, B.; Zhang, H.Q. Precision medicine for hepatocellular carcinoma: Driver mutations and targeted therapy. Oncotarget, 2017, 8(33), 55715-55730.
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2018. CA Cancer J. Clin., 2018, 68, 7-30.
Hashem, B.; El-Serag, M.D. Hepatocellular Carcinoma. N. Engl. J. Med., 2011, 365(12), 1118-1127.
Forner, A.; Llovet, J.M.; Bruix, J. Hepatocellular carcinoma. Lancet, 2012, 379, 1245-1255.
Tejedamaldonado, J.; Garcíajuárez, I.; Aguirrevaladez, J.; González-Aguirre, A.; Vilatobá-Chapa, M.; Armengol-Alonso, A. Diagnosis and treatment of hepatocellular carcinoma: An update. World J. Hepatol., 2015, 7(3), 362-376.
Llovet, J.M.; Real, M.I.; Montaña, X.; Planas, R.; Coll, S.; Aponte, J.; Ayuso, C.; Sala, M.; Muchart, J.; Solà, R.; Rodés, J.; Bruix, J. Barcelona liver cancer group. arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet, 2002, 359(9319), 1734-1739.
Le Grazie, M.; Biagini, M.R.; Tarocchi, M.; Polvani, S.; Galli, A. Chemotherapy for hepatocellular carcinoma: The present and the future. World J. Hepatol., 2017, 9(21), 907-920.
Yu, H.; Jove, R. The STATS of cancer-new molecular targets come of age. Nat. Rev. Cancer, 2004, 4(2), 97-105.
Miklossy, G.; Hilliard, T.S.; Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov., 2013, 12(8), 611-620.
Subramaniam, A.; Shanmugam, M.K.; Perumal, E.; Li, F.; Nachiyappan, A.; Dai, X.; Swamy, S.N.; Ahn, K.S.; Kumar, A.P.; Tan, B.K.H.; Hui, K.M.; Sethi, G. Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim. Biophys. Acta, 2013, 1835, 46-60.
Ghavami, S.; Hashemi, M.; Ande, S.R.; Yeganeh, B.; Xiao, W.; Eshraghi, M.; Bus, C.J.; Kadkhoda, K.; Wiechec, E.; Halayko, A.J.; Los, M. Apoptosis and cancer: Mutations within caspase genes. J. Med. Genet., 2009, 46, 497-510.
Yue, P.; Turkson, J. Targeting STAT3 in cancer: How successful are we? Expert Opin. Investig. Drugs, 2009, 18(1), 45-56.
Song, S.; Jung, Y.Y.; Hwang, C.J.; Lee, H.P.; Sok, C.H.; Kim, J.H.; Lee, S.M.; Seo, H.O. Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-κB activation in cultured astrocytes and microglial BV-2 cells. J. Neuroinflammation, 2014, 11, 118.
Zhang, X.; Zhang, J.; Tong, L.J.; Luo, Y.; Su, M.; Zang, Y.; Li, J.; Lu, W.; Chen, Y. The discovery of colchicine-SAHA hybrids as a new class of antitumor agents. Bioorg. Med. Chem., 2013, 21(11), 3240-3244.
Zhang, L.; Wang, X.J.; Li, X.G.; Zhang, L.; Xu, W. Discovery of a series of hydroximic acid derivatives as potent histone deacetylase inhibitors. J. Enzyme Inhib. Med. Chem., 2014, 29(4), 582-589.
Yue, P.; Lopez-Tapia, F.; Paladino, D.; Li, Y.; Chen, C.H.; Hilliard, T.; Chen, Y.; Tius, M.A.; Turkson, J. Hydroxamic acid and benzoic acid-based Stat3 inhibitors suppress human glioma and breast cancer phenotypes in vitro and in vivo. Cancer Res., 2016, 76(3), 652-663.
Kurokawa, M.; Kornbluth, S. Caspases and kinases in a death grip. Cell, 2009, 138(5), 838-854.
Masuda, M.; Suzui, M.; Yasumatu, R.; Nakashima, T.; Kuratomi, Y.; Azuma, K.; Tomita, K.; Komiyama, S.; Weinstein, I.B. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res., 2002, 62(12), 3351-3355.
Nowakowska, A.; Tarasiuk, J. Invasion and metastasis of tumor cells resistant to chemo-therapy. Postepy Hig. Med. Dosw., 2017, 71, 380-397.
Jabłońskatrypuć, A.; Matejczyk, M.; Rosochacki, S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzyme Inhib. Med. Chem., 2016, 31, 177-183.
Xie, T.X.; Wei, D.; Liu, M.; Gao, A.C.; Ali-Osman, F.; Sawaya, R.; Huang, S. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004, 23(20), 3550-3560.
Liao, T.T.; Yang, M.H. Revisiting epithelial-mesenchymal transition in cancer metastasis: The connection between epithelial plasticity and stemness. Mol. Oncol., 2017, 11(7), 792-804.
Wang, R.A.; Li, Q.; Li, Z.S.; Zheng, P.J.; Zhang, H.Z.; Huang, X.F.; Chi, S.M.; Yang, A.G.; Cui, R. Apoptosis drives cancer cells proliferate and metastasize. J. Cell. Mol. Med., 2013, 17(1), 205-211.
Siveen, K.S.; Sikka, S.; Surana, R.; Dai, X.; Zhang, J.; Kumar, A.P.; Tan Benny, K.H.; Sethi, G.; Bishayee, A. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim. Biophys. Acta, 2014, 1845(2), 136-154.
Frenette, C.; Gish, R. Targeted systemic therapies for hepatocellular carcinoma: Clinical perspectives, challenges and implications. World J. Gastroenterol., 2012, 18(6), 498-506.
Van Zijl, F.; Krupitza, G.; Mikulits, W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat. Res., 2011, 728(1-2), 23-34.
Li, W.C.; Ye, S.L.; Sun, R.X.; Liu, Y.K.; Tang, Z.Y.; Kim, Y.; Karras, J.G.; Zhang, H. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin. Cancer Res., 2006, 12(23), 7140-7148.
Xie, D.; Gore, C.; Liu, J.; Pong, R.C.; Mason, R.; Hao, G.; Long, M.; Kabbani, W.; Yu, L.; Zhang, H.; Chen, H.; Sun, X.; Boothman, D.A.; Min, W.; Hsieh, J.T. Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proc. Natl. Acad. Sci. USA, 2010, 107(6), 2485-2490.
Tania, M.; Khan, M.A.; Fu, J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumour Biol., 2014, 35(8), 7335-7342.
Overall, C.M.; Kleifeld, O. Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer, 2006, 6(3), 227-239.
Debnath, B.; Xu, S.; Neamati, N. Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J. Med. Chem., 2012, 55(15), 6645-6668.

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Article Details

Year: 2019
Published on: 01 August, 2019
Page: [583 - 593]
Pages: 11
DOI: 10.2174/1568009619666181226094814
Price: $65

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