药学学报, 2022, 57(5): 1344-1351
引用本文:
赵梓圳, 付琛, 崔志鸿, 李晓荣, 张颖颖, 张雨萍, 杨晓茜, 付爱玲*. 质子型双菲啰啉的特异性抗肿瘤活性及其机制研究[J]. 药学学报, 2022, 57(5): 1344-1351.
ZHAO Zi-zhen, FU Chen, CUI Zhi-hong, LI Xiao-rong, ZHANG Ying-ying, ZHANG Yu-ping, YANG Xiao-xi, FU Ai-ling*. Specific antitumor activity and mechanism of protonic bis-phenanthroline[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1344-1351.

质子型双菲啰啉的特异性抗肿瘤活性及其机制研究
赵梓圳, 付琛, 崔志鸿, 李晓荣, 张颖颖, 张雨萍, 杨晓茜, 付爱玲*
西南大学药学院, 重庆 400716
摘要:
肝细胞癌(hepatocellular carcinoma,HCC)是常见的恶性肿瘤,其发病率高且极易转移复发,严重影响人类健康。传统药物治疗存在不良反应大、多药耐药等问题,因此亟须寻找新的药物和作用靶点。本研究合成了质子型的双菲啰啉(protonic bis-phenanthroline,H-BP),结果显示H-BP可选择性地抑制肿瘤细胞增殖,引起肝癌细胞凋亡;在HCC荷瘤小鼠体内,H-BP能够有效阻止瘤块的生长,在中剂量(5 mg·kg-1)和高剂量(10 mg·kg-1)时甚至可完全消除肿瘤,并对小鼠体重没有明显影响。实验方案由西南大学动物实验伦理委员会批准,严格按照动物使用和护理的伦理原则进行实验操作。机制研究表明,H-BP引起HCC凋亡的原因与H-BP降低了原癌基因转录因子多形性腺瘤基因样蛋白2(pleomorphic adenoma gene like-2,PLAGL2)的表达有关,造成PLAGL2下游蛋白缺氧诱导因子和β连环蛋白的下调,从而引发癌细胞死亡。本研究不仅使用氢键二聚化方法合成化合物,为药物的设计提供新的思路,而且实验结果表明PLAGL2可能是肿瘤治疗中的一个有效靶标。
关键词:    肝细胞癌      质子型双菲啰啉      多形性腺瘤基因样蛋白2      凋亡      氢键     
Specific antitumor activity and mechanism of protonic bis-phenanthroline
ZHAO Zi-zhen, FU Chen, CUI Zhi-hong, LI Xiao-rong, ZHANG Ying-ying, ZHANG Yu-ping, YANG Xiao-xi, FU Ai-ling*
College of Pharmaceutical Science, Southwest University, Chongqing 400716, China
Abstract:
Hepatocellular carcinoma (HCC) is a common malignant tumor worldwise. The incidence rate of HCC is high and is easy to metastasis and recurrence, which seriously affects human health. Traditional chemical drugs have some challenges such as toxicity, side effects, and multidrug resistance, thus it is urgent to find new drugs and effective targets. Here we synthesized a novel chemical, protonic bis-phenanthroline (H-BP), and the antitumor effect was investigated in the study. The results showed that H-BP could selectively inhibit the proliferation of tumor cells and cause HCC apoptosis. And also, in HCC tumor-bearing mice, H-BP could effectively prevent the growth of tumor mass, even completely eliminate the tumor at medium dose (5 mg·kg-1) and high dose (10 mg·kg-1), and meanwhile H-BP has no significant effect on the body weight of mice. The experimental protocol was approved by the Animal Ethics Committee of Southwest University, and the experimental operation was strictly carried out in accordance with the ethical principles of animal use and care. Mechanism studies showed that H-BP induced HCC apoptosis was related to down-regulation the expression of pleomorphic adenoma gene like-2 (PLAGL2), a oncogene transcription factor, resulting in the down-regulation of PLAGL2 downstream proteins hypoxia inducible factor and β-catenin. This study not only introduces the dimerization method to form novel compounds that will provide a new approach for drug design, but also suggests that PLAGL2 may be an effective target in tumor therapy.
Key words:    hepatocellular carcinoma    protonic bis-phenanthroline    pleomorphic adenoma gene like-2    apoptosis    hydrogen bond   
收稿日期: 2021-10-31
DOI: 10.16438/j.0513-4870.2021-1553
基金项目: 国家自然科学基金资助项目(82073830);重庆市基础研究与前沿探索重点项目(cstc2019jcyj-zdxmX0035);中央高校基本业务费项目(7110100301).
通讯作者: 付爱玲,Tel/Fax:86-23-68251225,E-mail:fal@swu.edu.cn
Email: fal@swu.edu.cn
相关功能
PDF(935KB) Free
打印本文
0
作者相关文章
赵梓圳  在本刊中的所有文章
付琛  在本刊中的所有文章
崔志鸿  在本刊中的所有文章
李晓荣  在本刊中的所有文章
张颖颖  在本刊中的所有文章
张雨萍  在本刊中的所有文章
杨晓茜  在本刊中的所有文章
付爱玲*  在本刊中的所有文章

参考文献:
[1] Zhao Z, Fu C, Zhang Y, et al. Dimeric histidine as a novel free radical scavenger alleviates non-alcoholic liver injury[J]. Anti-oxidants, 2021, 10:1529.
[2] Xun HR, Liu B, Wang SQ, et al. Sodium nitrite improves epithelial-mesenchymal transition of hepatoma cells in mice bearing H22[J]. Acta Pharm Sin (药学学报), 2012, 47:1470-1476.
[3] Chen XY, Liu JT, Deng HM, et al. Effect on tumor growth inhibition activity of Gekkoswinhonis Guenther with different extent of broiling on H22 tumor-bearing mice[J]. Acta Pharm Sin (药学学报), 2019, 54:1048-1053.
[4] Ji G, Ma L, Yao H, et al. Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy[J]. Acta Pharm Sin B, 2020, 10:2171-2182.
[5] Ozeryanskii VA, Marchenko AV, Pozharskii F, et al. Combination of "buttressing" and "clothespin" effects for reaching the shortest NHN hydrogen bond in proton sponge cations[J]. J Org Chem, 2021, 4:3637-3647.
[6] Alder RW, Bowman PS, Steele WRS, et al. The remarkable basicity of 1,8-bis(dimethylamino)naphthalene[J]. Chem Comm, 1968, 13:723-724.
[7] Karas LJ, Wu CH, Das R, et al. Hydrogen bond design principles[J]. Wiley Interdiscip Rev Comput Mol Sci, 2020, 10:e1477.
[8] Strubberg AM, Paniagua DAV, Zhao T, et al. The zinc finger transcription factor PLAGL2 enhances stem cell fate and activates expression of ASCL2 in intestinal epithelial cells[J]. Stem Cell Rep, 2018, 11:410-424.
[9] Hu W, Zheng S, Guo H, et al. PLAGL2-EGFR-HIF-1/2α signaling loop promotes HCC progression and erlotinib insensitivity[J]. Hepatology, 2020, 73:674-691.
[10] Cao Y, Tao Q, Kao X, et al. Hsa-circRNA-103809 promotes hepatocellular carcinoma development via microRNA-1270/PLAG1 like zinc finger 2 axis[J]. Dig Dis Sci, 2021, 66:1524-1532.
[11] Su C, Li D, Li N, et al. Studying the mechanism of PLAGL2 overexpression and its carcinogenic characteristics based on 3'-untranslated region in colorectal cancer[J]. Int J Oncol, 2018, 52:1479-1490.
[12] Liu B, Lu C, Song YX, et al. The role of pleomorphic adenoma gene-like 2 in gastrointestinal cancer development, progression, and prognosis[J]. Int J Clin Exp Pathol, 2014, 7:3089-3100.
[13] Yang T, Huo J, Xu R, et al. Selenium sulfide disrupts the PLAGL2/C-MET/STAT3-induced resistance against mitochondrial apoptosis in hepatocellular carcinoma[J]. Clin Transl Med, 2021, 11:e536.
[14] Li T, Mao C, Wang X, et al. Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation[J]. J Exp Clin Cancer Res, 2020, 39:224.
[15] Kim E, Lisby A, Ma C, et al. Promotion of growth factor signaling as a critical function of β-catenin during HCC progression[J]. Nat Commun, 2019, 10:1909.
[16] Wang L, Sun L, Liu R, et al. Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression[J]. J Exp Clin Cancer Res, 2021, 40:72.
[17] Wu L, Zhou Z, Han S, et al. PLAGL2 promotes epithelial-mesenchymal transition and mediates colorectal cancer meta-stasis via β-catenin-dependent regulation of ZEB1[J]. Br J Cancer, 2020, 122:578-589.
[18] Wang YP, Guo PT, Zhu Z, et al. Pleomorphic adenoma gene like-2 induces epithelial-mesenchymal transition via Wnt/β‍-catenin signaling pathway in human colorectal adenocarcinoma[J]. Oncol Rep, 2017, 37:1961-1970.
相关文献:
1.叶汉林, 乔淦, 王琳琳, 程丽, 林秀坤*.原阿片碱通过线粒体凋亡途径抑制肝细胞癌生长[J]. 药学学报, 2021,56(8): 2223-2229
2.肖斌, 张璇, 张美兰, 张学武.珍珠梅黄酮纳米粒抑制人肝癌HepG-2细胞STAT3诱导细胞凋亡[J]. 药学学报, 2016,51(12): 1845-1851