N-异喹啉-3-羧酸-L-亮氨酸苄酯抗人食道癌作用的研究

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (8): 877-881.

N-异喹啉-3-羧酸-L-亮氨酸苄酯抗人食道癌作用的研究

杨国栋¹, 张晓英², 冯志松¹, 贺国斌¹, 江毅敏¹

¹ 川北医学院附属医院消化内科,南充 637000,四川;
² 川北医学院寄生虫教研室,南充 637000,四川

收稿日期:2014-01-02 修回日期:2014-07-21 出版日期:2014-08-26 发布日期:2014-08-26
通讯作者: 张晓英，女，博士，讲师，研究方向：肿瘤基础研究。 Tel:15881722608 E-mail:zxy269163@.com
作者简介:杨国栋，男，博士，主治医师，讲师，研究方向：消化道肿瘤。Tel:15860569639 E-mail:ygd_ld2003@.com
基金资助:
川北医学院科研发展重点培育项目（CBY13-A-ZP16）；川北医学院2013年博士科研启动基金（CBY13-QD-12）

N-isoquinoline-3-carbonyl-L-Leucine-benzylester as a new agent of inhibiting esophageal carcinoma proliferation

YANG Guo-dong¹, ZHANG Xiao-ying², FENG Zhi-song¹, HE Guo-bin¹, JIANG Yi-min¹

¹ Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China;
² Teaching and Research Section of Parasitology, School of Basic Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan, China

Received:2014-01-02 Revised:2014-07-21 Online:2014-08-26 Published:2014-08-26

摘要/Abstract

摘要： 目的体内外研究N-异喹啉-3-羧酸-L-亮氨酸苄酯(N-isoquinoline-3-carbonyl-L-Leucine- benzylester,IQ-L-OBzl)对人食道癌细胞体抗肿瘤作用。方法 MTT法检测细胞活性;检测食管癌裸鼠移植瘤模型的瘤重,计算抑瘤率及外周血白细胞数;流式细胞仪检测细胞内活性氧(intracellular reactive oxygen species, ROS)的水平。结果在体外实验中IQ-L-OBzl组的食管癌(Eca-109、EC-9706)IC₅₀分别为(405.06±23.49) nmol/L、(485.79±48.47) nmol/L;体内实验中最高抑瘤率为(42.42±7.47) %,化合物的抑瘤率及瘤重有明显的浓度相关性;IQ-L-OBzl组细胞内ROS水平为(98.68±13.19)平均荧光强度(MFI),高于对照组(P<0.05)。结论 IQ-L-OBzl的体内、外抗食道癌作用与细胞内ROS有关,且对白细胞无明显毒副作用。

关键词: N-异喹啉-3-羧酸-L-亮氨酸苄酯, 食道癌, 活性氧

Abstract: AIM: To determine whether N-isoquinoline-3-carbonyl-L-Leucine-benzylester(IQ-L-OBzl)inhibited the growth of human esophageal cancer cell in vitro and in vivo. METHODS: MTT assays were performed to assess the proliferation of esophageal carcinoma cell lines. The model of esophageal carcinoma in nude mice was established, then the weight of tumor tissue was measured, the growth inhibition rates of tumor were calculated and the WBC were counted on peripheral blood of the mice. Intracellular reactive oxygen species(ROS)were detected by flow cytometry analysis. RESULTS: The IC₅₀ of IQ-L-OBzl inhibiting esophageal carcinoma cell lines(Eca-109 and EC-9706)proliferation were (405.06±23.49) nmol/L and (485.79±48.47) nmol/L. The best growth inhibition rate was (42.42±7.47) %. The growth inhibition rate and the weight of tumor exhibited dose-dependent manner. The ROS level of IQ-L-OBzl was (98.68±13.19) MFI, higher than that in control groups (P<0.05). CONCLUSION: IQ-L-OBzl has anti-esophageal carcinoma ability in vitro and in vivo, and this ability have related to ROS without significant side effects on WBC.

Key words: N-isoquinoline-3-carbonyl-L-Phenylalanine-benzylester, esophageal carcinoma, reactive oxygen species

中图分类号:

R735.1

杨国栋, 张晓英, 冯志松, 贺国斌, 江毅敏. N-异喹啉-3-羧酸-L-亮氨酸苄酯抗人食道癌作用的研究[J]. 中国临床药理学与治疗学, 2014, 19(8): 877-881.

YANG Guo-dong, ZHANG Xiao-ying, FENG Zhi-song, HE Guo-bin, JIANG Yi-min. N-isoquinoline-3-carbonyl-L-Leucine-benzylester as a new agent of inhibiting esophageal carcinoma proliferation[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(8): 877-881.

参考文献 19

[1]	He YF, Ji CS, Hu B, et al.A phase II study of paclitaxel and nedaplatin as front-line chemotherapy in Chinese patients with metastatic esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2013, 19(35): 5910-5916.
[2]	Cui X, Chen Y, Liu L, et al.Heterozygote of PLCE1 rs2274223 increases susceptibility to human papillomavirus infection in patients with esophageal carcinoma among the Kazakh populations[J]. J Med Virol, 2013,10(2): 1-10.
[3]	Liu F, Wang JG, Wang SY, et al.Antitumor effect and mechanism of Gecko on human esophageal carcinoma cell lines in vitro and xenografted sarcoma 180 in Kunming mice[J]. World J Gastroenterol, 2008, 14(25): 3990-3996.
[4]	Shiozaki A, Nakashima S, Ichikawa D, et al.Prognostic significance of p21 expression in patients with esophageal squamous cell carcinoma[J]. Anticancer Res, 2013, 33(10): 4329-4335.
[5]	Hou X, Wei JC, Fu JH, et al.Proposed modification of the seventh american joint committee on cancer staging system for esophageal squamous cell carcinoma in Chinese patients[J]. Ann Surg Oncol, 2013,21(1): 337-342.
[6]	任志, 李龙, 付茂勇. 食管胃手工分层吻合术治疗食管癌、食管胃交界部癌的疗效观察[J]. 川北医学院学报, 2012, 27(1): 10-12.
[7]	Nagasaki E, Yuda M, Tanishima Y, et al.Complete response of esophageal small cell carcinoma amrubicin treatment[J]. J Infect Chemother, 2013, 19(4): 770-775.
[8]	Zheng M, Yang Y, Zhao M, et al.A class of novel N-isoquinoline-3-carbonyl-L-amino acid benzylesters: synthesis, anti-tumor evaluation and 3D QSAR analysis[J]. Eur J Med Chem, 2011, 46(5): 1672-1681.
[9]	Ferraroni M, Bazzicalupi C, Bilia AR, et al.X-Ray diffraction analyses of the natural isoquinoline alkaloids Berberine and sanguinarine complexed with double helix DNA d(CGTACG)[J]. Chem Commun (Camb), 2011, 47(17): 4917-4919.
[10]	Bhadra K, Kumar GS.Isoquinoline alkaloids and their binding with DNA: calorimetry and thermal analysis applications[J]. Mini Rev Med Chem, 2010, 10(13): 1235-1247.
[11]	Bhadra K, Maiti M, Kumar GS.Interaction of isoquinoline alkaloids with polymorphic DNA structures[J]. Chem Biodivers, 2009, 6(9): 1323-1242.
[12]	Ikeda R, Kitagawa S, Chiba J, et al.Electrochemical genotyping by using two ferrocene/isoquinoline- connected DNA probes with different redox potentials on a single electrode[J]. Chemistry, 2009, 15(29): 7048-7051.
[13]	Ikeda R, Kobayashi S, Chiba J, et al.Detection of mismatched duplexes by synchronizing the pulse potential frequency with the dynamics of ferrocene/isoquinoline conjugate-connected DNA probes immobilized onto electrodes[J]. Chemistry, 2009, 15(19): 4822-4828.
[14]	Shen L, Ji HF.The mechanisms of ROS-photogeneration by berberine, a natural isoquinoline alkaloid[J]. J Photochem Photobiol B, 2010, 99(3): 154-156.
[15]	Novotny J, Aziz N, Rybar R, et al.Relationship between reactive oxygen species production in human semen and sperm DNA damage assessed by Sperm Chromatin Structure Assay[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2013,157(4): 383-386.
[16]	Ni Q, Xu G, Gao Q, et al.Evaluation of reactive oxygen species scavenging activities and DNA damage prevention effect of Pleioblastus kongosanensis f. aureostriatus leaf extract by chemiluminescence assay[J]. J Photochem Photobiol B, 2013, 128: 115-121.
[17]	田东,贺巧,王洋,等.食管癌高发区农村居民饮食状况及对食管癌认知调查[J]. 川北医学院学报,2010,25(5):470-473.
[18]	杨国栋,吴静,强占荣,等. D-氨基葡萄糖衍生物对Eca-109细胞内活性氧、线粒体膜电位的影响[J]. 中国临床药理学与治疗学,2007,12(5):544-547.
[19]	黄文芳,曾娅莉,刘华,等. 辛伐他汀诱导K562细胞凋亡及对细胞内活性氧和Ca2+动态变化的影响[J]. 中国临床药理学与治疗学,2006,11(12):1364-1368.