氯硝柳胺乙醇胺联合埃克替尼体外对肺腺癌HCC827细胞的协同抗肿瘤效应
In Vitro Synergistic Antitumor Effect of Niclosamide Ethanolamine Combined with Icotinib on HCC827 Cell
DOI: 10.12677/ACM.2020.107186, PDF,   
作者: 张 君, 王红梅:青岛大学附属医院呼吸内科,山东 青岛
关键词: 氯硝柳胺乙醇胺盐酸埃克替尼协同抗肿瘤Chloronitramine Ethanolamine Icotinib Synergistic Antitumor
摘要: 目的:明确氯硝柳胺乙醇胺与盐酸埃克替尼联合应用在体外对人肺腺癌HCC827细胞的增殖抑制作用,探索两药合用是否具有协同抗肿瘤效应。方法:确定盐酸埃克替尼的半数抑制浓度、氯硝柳胺乙醇胺的半数抑制浓度,根据已确定的氯硝柳胺乙醇胺的IC50固定三个浓度,考察HCC827细胞增殖受到的抑制情况。绘制两药联合对HCC827细胞增殖的抑制曲线,检测两药是否有协同效应。结果:盐酸埃克替尼对HCC827细胞的IC50为0.61 μM。氯硝柳胺乙醇胺对HCC827细胞的IC50为0.46 μM。两药联用时,氯硝柳胺乙醇胺1.0 μM的处理组对细胞的抑制作用最明显,在极低浓度下细胞的生长即可被明显抑制。盐酸埃克替尼、氯硝柳胺均可以促进HCC827的细胞凋亡。联合应用组与单独应用组相比,HCC827细胞的晚期凋亡和坏死的比例都有所增加。结论:氯硝柳胺乙醇胺对人肺癌HCC827细胞株的增殖具有抑制作用,氯硝柳胺乙醇胺联合盐酸埃克替尼对人肺癌HCC827细胞有协同促进凋亡的作用。
Abstract: Objective: To investigate the inhibitory effect of clonsalimine ethanolamine and ectinib hydrochloride on HCC827 cells in human lung adenocarcinoma in vitro and explore whether the combination of the two drugs has a synergistic anti-tumor effect. Methods: The half inhibitory concentration of ectinib hydrochloride and the half inhibitory concentration of niclosamine ethanolamine were determined, and the inhibition of HCC827 cell proliferation was investigated according to the fixed IC50 concentration of niclosamine ethanolamine. The inhibition curve of the combination of two drugs on HCC827 cell proliferation was drawn to detect the synergistic effect of the two drugs. Results: The IC50 of ectinib hydrochloride on HCC827 cells was 0.61 M. The IC50 of niclosamide ethanolamine against HCC827 cells was 0.46 M. When the two drugs were used together, the inhibition of cell growth was the most obvious in the treatment group of 1 M of niclosamide ethanolamine, and the growth of cells was significantly inhibited at very low concentration. Both ectinib hydrochloride and niclosamine could promote apoptosis of HCC827 cells. The ratio of late apoptosis and necrosis of HCC827 cells was increased in the combined group compared with the single group. Conclusion: Clonsalimine ethanolamine can inhibit the proliferation of HCC827 cell lines in human lung cancer, and clonsalimine ethanolamine combined with ectinib hydrochloride can promote the apoptosis of HCC827 cell lines in human lung cancer.
文章引用:张君, 王红梅. 氯硝柳胺乙醇胺联合埃克替尼体外对肺腺癌HCC827细胞的协同抗肿瘤效应[J]. 临床医学进展, 2020, 10(7): 1211-1220. https://doi.org/10.12677/ACM.2020.107186

参考文献

[1] Zhang, X., Liu, S., Liu, Y., et al. (2017) Economic Burden for Lung Cancer Survivors in Urban China. International Journal of Environmental Research and Public Health, 14, 308. [Google Scholar] [CrossRef] [PubMed]
[2] Barnfield, P.C. and Ellis, P.M. (2016) Second-Line Treatment of Non-Small Cell Lung Cancer: New Developments for Tumours Not Harbouring Targetable Oncogenic Driver Mutations. Drugs, 76, 1321-1336. [Google Scholar] [CrossRef] [PubMed]
[3] Ramalingam, S. and Belani, C. (2008) Systemic Chemotherapy for Advanced Non-Small Cell Lung Cancer: Recent Advances and Future Directions. Oncologist, 13, 5-13. [Google Scholar] [CrossRef
[4] Schiller, J.H., Harrington, D., Belani, C.P., et al. (2002) Comparison of Four Chemotherapy Regimens for Advanced Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 346, 92-98. [Google Scholar] [CrossRef
[5] Greenhalgh, J., Dwan, K., Boland, A., et al. (2016) First-Line Treatment of Advanced Epidermal Growth Factor Receptor (EGFR) Mutation Positive Non-Squamous Non-Small Cell Lung Cancer. Cochrane Database of Systematic Reviews, 5, CD010383. [Google Scholar] [CrossRef
[6] Shi, Y., Zhang, L., Liu, X., et al. (2013) Icotinib versus Gefitinib in Previously Treated Advanced Non-Small-Cell Lung Cancer (ICOGEN): A Randomised, Double-Blind Phase 3 Non-Inferiority Trial. Lancet Oncology, 14, 953-961. [Google Scholar] [CrossRef
[7] Li, L., Han, R., Xiao, H., et al. (2014) Metformin Sensitizes EGFR-TKI-Resistant Human Lung Cancer Cells in Vitro and in Vivo through Inhibition of IL-6 Signaling and EMT Reversal. Clinical Cancer Research, 20, 2714-2726. [Google Scholar] [CrossRef
[8] Li, J. and Wang, X.H. (2020) Combined Treatment with N-Acetylcysteine and Gefitinib Overcomes Drug Resistance to Gefitinib in NSCLC Cell Line. Cancer Medicine, 9, 1495-1502. [Google Scholar] [CrossRef] [PubMed]
[9] Zhang, Y., Lv, C., Dong, Y., et al. (2020) Aspirin-Targeted PD-L1 in Lung Cancer Growth Inhibition. Thoracic Cancer, 11, 1587-1593.
[10] Chuang, S.-E. (2013) Aspirin Antagonizes the Cytotoxic Effect of Methotrexate in Lung Cancer Cells. Oncology Reports, 30, 1497-1505. [Google Scholar] [CrossRef] [PubMed]
[11] Andrews, P., Thyssen, J. and Lorke, D. (1982) The Biology and Toxicology of Molluscicides, Bayluscide. Pharmacology & Therapeutics, 19, 245-295. [Google Scholar] [CrossRef
[12] Al-Hadiya, B.M.H. (2005) Niclosamide: Comprehensive Profile. Profiles of Drug Substances, Excipients and Related Methodology, 32, 67-96. [Google Scholar] [CrossRef
[13] Jin, Y., Lu, Z., Ding, K., et al. (2010) Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem Cells: Inactivation of the NF-kB Pathway and Generation of Reactive Oxygen Species. Cancer Research, 70, 2516-2527. [Google Scholar] [CrossRef
[14] Osada, T., Chen, M., Yang, X.Y., et al. (2011) Antihelminth Compound Niclosamide Downreguates WNT Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations. Cancer Research, 71, 4172-4182. [Google Scholar] [CrossRef
[15] Sack, U., Walther, W., Scudiero, D., et al. (2011) Novel Effect of Antihelminthic Niclosamide on S100A4-Mediated Metastatic Progression in Colon Cancer. Journal of the National Cancer Institute, 103, 1018-1036. [Google Scholar] [CrossRef] [PubMed]
[16] Ren, X., Duan, L., He, Q., et al. (2010) Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway. ACS Medicinal Chemistry Letters, 1, 454-459. [Google Scholar] [CrossRef] [PubMed]
[17] Liu, Z., Li, Y., Lv, C., et al. (2016) Anthelmintic Drug Niclosamide Enhances the Sensitivity of Chronic Myeloid Leukemia Cells to Dasatinib through Inhibiting Erk/Mnk1/eIF4E Pathway. Biochemical and Biophysical Research Communications, 478, 893-899. [Google Scholar] [CrossRef] [PubMed]
[18] Arend, R.C., Londoño-Joshi, A.I., Samant, R.S., et al. (2014) Inhibition of Wnt/β-Catenin Pathway by Niclosamide: A Therapeutic Target for Ovarian Cancer. Gynecologic Oncology, 134, 112-120. [Google Scholar] [CrossRef] [PubMed]
[19] Park, S.J., Shin, J.H., Kang, H., et al. (2011) Niclosamide Induces Mitochondria Fragmentation and Promotes Both Apoptotic and Autophagic Cell Death. BMB Reports, 44, 517-522. [Google Scholar] [CrossRef
[20] Li, R., Hu, Z., Sun, S.Y., et al. (2013) Niclosamide Overcomes Acquired Resistance to Erlotinib through Suppression of STAT3 in Non-Small Cell Lung Cancer. Molecular Cancer Therapeutics, 12, 2200-2212. [Google Scholar] [CrossRef
[21] Li, R., You, S., Hu, Z., et al. (2013) Inhibition of STAT3 by Niclosamide Synergizes with Erlotinib against Head and Neck Cancer. PLoS One, 8, e74670. [Google Scholar] [CrossRef] [PubMed]
[22] Li, Y., Li, P.K., Roberts, M.J., et al. (2014) Multi-Targeted Therapy of Cancer by Niclosamide: A New Application for an Old Drug. Cancer Letters, 349, 8-14. [Google Scholar] [CrossRef] [PubMed]
[23] Yo, Y.-T., Lin, Y.-W., Wang, Y.-C., et al. (2012) Growth Inhibition of Ovarian Tumor-Initiating Cells by Niclosamide. Molecular Cancer Therapeutics, 11, 1703-1712. [Google Scholar] [CrossRef
[24] Liu, J., Chen, X., Ward, T., et al. (2016) Combined Niclosamide with Cisplatin Inhibits Epithelial Mesenchymal Transition and Tumor Growth in Cisplatin-Resistant Triple-Negative Breast Cancer. Tumor Biology, 37, 9825-9835. [Google Scholar] [CrossRef] [PubMed]
[25] Wang, Y.-C., Chao, T.-K., Chang, C.-C., et al. (2013) Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells. PLoS One, 8, e74538. [Google Scholar] [CrossRef] [PubMed]
[26] Chen, B., Wei, W., Ma, L., et al. (2017) Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells in Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling. Gastroenterology, 152, 2022-2036. [Google Scholar] [CrossRef] [PubMed]
[27] Lee, M.-C., Chen, Y.-K., Hsu, Y.-J., et al. (2020) Niclosamide Inhibits the Cell Proliferation and Enhances the Responsiveness of Esophageal Cancer Cells to Chemotherapeutic Agents. Oncology Reports, 43, 549-561.
[28] Chang, X., Zhen, X., Liu, J., et al. (2017) The Antihelmenthic Phosphate Niclosamide Impedes Renal Fibrosis by Inhibiting Homeodomain-Interacting Protein Kinase 2 Expression. Kidney International, 92, 612-624. [Google Scholar] [CrossRef] [PubMed]
[29] Kim, M.-O., Choe, M.H., Yoon, Y.N., et al. (2017) Antihelminthic Drug Niclosamide Inhibits CIP2A and Reactivates Tumor Suppressor Protein Phosphatase 2A in Non-Small Cell Lung Cancer Cells. Biochemical Pharmacology, 144, 78-89. [Google Scholar] [CrossRef] [PubMed]
[30] Gahr, S., Stoehr, R., Geissinger, E., et al. (2013) EGFR Mutational Status in a Large Series of Caucasian European NSCLC Patients: Data from Daily Practice. British Journal of Cancer, 109, 1821-1828. [Google Scholar] [CrossRef] [PubMed]
[31] Lee, M.C., Chen, Y.K., Hsu, Y.J., et al. (2020) Niclosamide Inhibits the CELL proliferation and Enhances the Responsiveness of Esophageal Cancer Cells to Chemotherapeutic Agents. Oncology Reports, 43, 549-561. [Google Scholar] [CrossRef] [PubMed]
[32] Pan, J.-X., Ding, K. and Wang, C.-Y. (2012) Niclosamide, an Old Antihelminthic Agent, Demonstrates Antitumor Activity by Blocking Multiple Signaling Pathways of Cancer Stem Cells. Chinese Journal of Cancer, 31, 178-184. [Google Scholar] [CrossRef] [PubMed]
[33] Chen, W., Mook Jr., R.A., Premont, R.T. and Wang, J.B. (2018) Niclosamide: Beyond an Antihelminthic Drug. Cellular Signalling, 41, 89-96. [Google Scholar] [CrossRef] [PubMed]
[34] You, S., Li, R., Park, D., et al. (2014) Disruption of STAT3 by Niclosamide Reverses Radioresistance of Human Lung Cancer. Molecular Cancer Therapeutics, 13, 606-616. [Google Scholar] [CrossRef
[35] Chai, W.-H., Li, Y.-R., Lin, S.-H., et al. (2020) In Vitro Antihelminthic Niclosamide Induces Autophagy and Delayed Apoptosis in Human Non-small Lung Cancer Cells and. Anticancer Research, 40, 1405-1417. [Google Scholar] [CrossRef] [PubMed]
[36] 左瑜芳, 杨东雁, 徐祖敏, 等. 氯硝柳胺对肺癌细胞株顺铂敏感性的影响[J]. 广东医科大学学报, 2017, 35(2): 144-147.
[37] Zuo, Y., Yang, D., Yu, Y., et al. (2018) Niclosamide Enhances the Cytotoxic Effect of Cisplatin in Cisplatin-Resistant Human Lung Cancer Cells via Suppression of Lung Resistance-Related Protein and c-myc. Molecular Medicine Reports, 17, 3497-3502.
[38] Helfman, D.M., Kim, E.J., Lukanidin, E. and Grigorian, M. (2005) The Metastasis Associated Protein S100A4: Role in Tumour Progression and Metastasis. British Journal of Cancer, 92, 1955-1958. [Google Scholar] [CrossRef] [PubMed]