药学学报, 2022, 57(5): 1396-1401
引用本文:
刘羿晨, 季鸣, 杜婷婷, 刘文强, 李莉, 陈晓光*. 新型STAT3小分子抑制剂LZJ541抑制肝癌细胞增殖的活性研究[J]. 药学学报, 2022, 57(5): 1396-1401.
LIU Yi-chen, JI Ming, DU Ting-ting, LIU Wen-qiang, LI Li, CHEN Xiao-guang*. Inhibitory effect of LZJ541, a novel small molecule inhibitor of STAT3, on the proliferation of hepatocellular carcinoma cells[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1396-1401.

新型STAT3小分子抑制剂LZJ541抑制肝癌细胞增殖的活性研究
刘羿晨, 季鸣, 杜婷婷, 刘文强, 李莉, 陈晓光*
中国医学科学院药物研究所, 天然药物活性物质与功能国家重点实验室, 创新药物非临床药物代谢及PK/PD研究北京市重点实验室, 活性物质发现与适药化北京市重点实验室, 北京 100050
摘要:
信号传导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)是细胞增殖转移的重要调节因子,参与多种恶性肿瘤的发生和发展,是目前靶向抗肿瘤药物研究的热点之一。本课题组通过两面神激酶(Janus kinase,JAK)/STAT3通路抑制剂筛选模型筛选得到了新型苯并二咪唑结构小分子化合物LZJ541,具有明确的STAT3抑制活性。通过MTT实验检测LZJ541对肝癌HepG2及前列腺癌PC-3细胞增殖能力的影响;通过Western blot实验检测其对肿瘤细胞中STAT3通路相关蛋白的影响;通过流式细胞术检测其对HepG2细胞凋亡水平及周期分布的影响。结果表明,LZJ541显著抑制STAT3信号通路的活化,能显著抑制HepG2细胞增殖,其半数抑制浓度(half maximal inhibitory concentration,IC50)为13.8 μmol·L-1,远低于STAT3低表达的PC-3细胞(IC50:41.99 μmol·L-1),LZJ541还可抑制HepG2细胞中STAT3蛋白的磷酸化,从而诱导细胞凋亡和周期阻滞,发挥抗肿瘤作用。综上,LZJ541具有一定的体外抗肿瘤作用,本研究为围绕这一化合物研发新型STAT3靶向抗肿瘤药物提供了实验依据。
关键词:    苯并二咪唑      IL6/JAK/STAT3信号通路      STAT3抑制剂      肝细胞癌      抗肿瘤药物     
Inhibitory effect of LZJ541, a novel small molecule inhibitor of STAT3, on the proliferation of hepatocellular carcinoma cells
LIU Yi-chen, JI Ming, DU Ting-ting, LIU Wen-qiang, LI Li, CHEN Xiao-guang*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China
Abstract:
Signal transducer and activator of transcription 3 (STAT3) is an important regulatory factor of cell proliferation and metastasis, involved in the occurrence and development of a variety of malignant tumors, and it is one of the hot spots in the research of targeted anti-tumor drugs. Our group screened a novel benzobis (imidazole) structure small molecule compound LZJ541 through the screening model of Janus kinase (JAK)/STAT3 pathway inhibitors, which has definite STAT3 inhibitory activity. We examined the effect of LZJ541 on the proliferation of HepG2 and PC-3 cells by MTT assay in vitro, detected the effect of LZJ541 on the expression of STAT3-related proteins in HepG2 cells by Western blot, and measured the effect of LZJ541 on the apoptosis and cell cycle arrest of HepG2 cells via flow cytometry. The results indicated that LZJ541 significantly inhibited the activation of STAT3 signaling pathway and restrained the proliferation of HepG2 cells. Its half maximal inhibitory concentration (IC50) was 13.8 μmol·L-1, which was much lower than that of PC-3 cells (with low STAT3 expression, IC50:41.99 μmol·L-1), LZJ541 can also inhibit the phosphorylation of STAT3 in HepG2 cells, thereby inducing apoptosis and cycle arrest and then exerting anti-tumor effects. In conclusion, LZJ541 has a certain anti-tumor effect in vitro, which provides an experimental basis for the development of new STAT3-targeted anti-tumor drugs around this kind of compounds.
Key words:    benzobis(imidazole)    IL6/JAK/STAT3 signaling pathway    STAT3 inhibitor    hepatocellular carcinoma    antineoplastic agent   
收稿日期: 2022-03-02
DOI: 10.16438/j.0513-4870.2022-0274
基金项目: 中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-026).
通讯作者: 陈晓光,Tel:86-10-63165207,E-mail:chxg@imm.ac.cn
Email: chxg@imm.ac.cn
相关功能
PDF(571KB) Free
打印本文
0
作者相关文章
刘羿晨  在本刊中的所有文章
季鸣  在本刊中的所有文章
杜婷婷  在本刊中的所有文章
刘文强  在本刊中的所有文章
李莉  在本刊中的所有文章
陈晓光*  在本刊中的所有文章

参考文献:
[1] Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells:a review[J]. Int J Cancer, 2016, 138:2570-2578.
[2] Ji Y, Liu Y, Xue N, et al. Cryptotanshinone inhibits esophageal squamous-cell carcinoma in vitro and in vivo through the suppression of STAT3 activation[J]. Onco Targets Ther, 2019, 12:883-896.
[3] Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy[J]. BMB Rep, 2019, 52:415-423.
[4] Yee NS. Update in systemic and targeted therapies in gastrointestinal oncology[J]. Biomedicines, 2018, 6:34.
[5] Boydston AJ, Vu PD, Dykhno OL, et al. Modular fluorescent benzobis(imidazolium) salts:syntheses, photophysical analyses, and applications[J]. J Am Chem Soc, 2008, 130:3143-3156.
[6] Ji M, Xue N, Huang R, et al. Validation and application a cell-based screening model for IL-6/JAK/STAT3 inhibitor[J]. Acta Pharm Sin (药学学报), 2018, 53:749-753.
[7] Xu L, Lao Y, Zhao Y, et al. Screening active compounds from garcinia species native to China reveals novel compounds targeting the STAT/JAK signaling pathway[J]. Biomed Res Int, 2015, 2015:910453.
[8] Jin Y, Chen X, Gao Z, et al. Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation[J]. Biomed Pharmacother, 2021, 144:112297.
[9] Zheng X, Xu K, Zhu L, et al. MiR-486-5p act as a biomarker in endometrial carcinoma:promotes cell proliferation, migration, invasion by targeting MARK1[J]. Onco Targets Ther, 2020, 13:4843-4853.
[10] Zhang Y, Lu W, Zhang X, et al. Cryptotanshinone protects against pulmonary fibrosis through inhibiting Smad and STAT3 signaling pathways[J]. Pharmacol Res, 2019, 147:104307.
[11] Chen Y, Ji M, Zhang S, et al. Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer[J]. J Drug Target, 2018, 26:920-930.
[12] Kao JT, Feng CL, Yu CJ, et al. IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients:a cohort study[J]. BMC Gastroenterol, 2015, 15:50.
[13] Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China:a secondary analysis of the global cancer statistics 2020[J]. Chin Med J (Engl), 2021, 134:783-791.
[14] Ko KL, Mak LY, Cheung KS, et al. Hepatocellular carcinoma:recent advances and emerging medical therapies[J]. F1000Res, 2020, 9:F1000Faculty Rev-620.
[15] Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma:a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391:1163-1173.
[16] Okusaka T, Ueno H, Ikeda M, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma[J]. Hepatol Res, 2015, 45:1283-1291.
[17] Wan S, Zhao E, Kryczek I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells[J]. Gastroenterology, 2014, 147:1393-1404.
[18] Liu Y, Luo YH, Li SM, et al. 2-(Naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via ROS-mediated MAPK, AKT, and STAT3 signaling pathways in HepG2 human hepatocellular carcinoma cells[J]. Drug Chem Toxicol, 2022, 45:33-43.