Login Register Cart 0
Generic placeholder image

当代肿瘤药物靶点

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in English
Research Article

EH-42：一种新型小分子通过抑制STAT3信号通路诱导细胞凋亡并抑制人肝癌细胞的迁移和侵袭

卷 19, 期 7, 2019

页: [583 - 593] 页: 11

弟呕挨: 10.2174/1568009619666181226094814

价格: $65

摘要

背景：由于信号转导和转录激活因子3（STAT3）在肝细胞癌（HCC）中异常激活，并在该肿瘤进展中起关键作用。 已经认为抑制STAT3信号传导途径是抑制HCC发展的有效治疗策略。 目的：在本研究中，我们研究了EH-42对HCC细胞的抗癌作用，并试图解释其潜在机制。 方法：采用MTT法，结肠形成法和AnnexinV-FITC / PI双染法检测EH-42对细胞生长和存活的影响。 进行伤口愈合测定和transwell侵袭测定以评估EH-42对细胞迁移和侵袭的影响。 进行蛋白质印迹分析以分析EH-42对相对蛋白质的影响。 结果：根据MTT法，结肠形成实验和AnnexinV-FITC / PI双染试验，EH-42能够以剂量依赖的方式抑制HCC细胞的生长并诱导其凋亡。 进一步的免疫印迹实验表明，EH-42对细胞生长和存活的抑制作用是通过激活caspase 3/9，抑制磷酸化STAT3（Tyr 705）和下调抗凋亡蛋白如Bcl-2 / Bcl-xL引起的。 此外，在伤口愈合测定和transwell侵袭测定中，EH-42也抑制HCC细胞的迁移和侵袭能力。 潜在的机制是EH-42可通过逆转上皮 - 间质转化和下调MMPs的分泌来抑制HCC转移。 结论：总之，这些发现表明EH-42可能是HCC治疗的潜在治疗药物。

关键词: STAT3，细胞凋亡，迁移，侵袭，肝细胞癌。

« Previous
图形摘要

[1]
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.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2018. CA Cancer J. Clin., 2018, 68, 7-30.
[3]
Hashem, B.; El-Serag, M.D. Hepatocellular Carcinoma. N. Engl. J. Med., 2011, 365(12), 1118-1127.
[4]
Forner, A.; Llovet, J.M.; Bruix, J. Hepatocellular carcinoma. Lancet, 2012, 379, 1245-1255.
[5]
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.
[6]
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.
[7]
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.
[8]
Yu, H.; Jove, R. The STATS of cancer-new molecular targets come of age. Nat. Rev. Cancer, 2004, 4(2), 97-105.
[9]
Miklossy, G.; Hilliard, T.S.; Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov., 2013, 12(8), 611-620.
[10]
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.
[11]
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.
[12]
Yue, P.; Turkson, J. Targeting STAT3 in cancer: How successful are we? Expert Opin. Investig. Drugs, 2009, 18(1), 45-56.
[13]
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.
[14]
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.
[15]
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.
[16]
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.
[17]
Kurokawa, M.; Kornbluth, S. Caspases and kinases in a death grip. Cell, 2009, 138(5), 838-854.
[18]
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.
[19]
Nowakowska, A.; Tarasiuk, J. Invasion and metastasis of tumor cells resistant to chemo-therapy. Postepy Hig. Med. Dosw., 2017, 71, 380-397.
[20]
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.
[21]
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.
[22]
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.
[23]
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.
[24]
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.
[25]
Frenette, C.; Gish, R. Targeted systemic therapies for hepatocellular carcinoma: Clinical perspectives, challenges and implications. World J. Gastroenterol., 2012, 18(6), 498-506.
[26]
Van Zijl, F.; Krupitza, G.; Mikulits, W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat. Res., 2011, 728(1-2), 23-34.
[27]
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.
[28]
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.
[29]
Tania, M.; Khan, M.A.; Fu, J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumour Biol., 2014, 35(8), 7335-7342.
[30]
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.
[31]
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.

Rights & Permissions Print Cite
Article Metrics
88
4
1
© 2024 Bentham Science Publishers | Privacy Policy