抗耐药长春瑞滨脂质体及其抗耐药性乳腺癌的效应与机制研究

doi:10.5246/jcps.2016.07.054

中国药学(英文版) ›› 2016, Vol. 25 ›› Issue (7): 489-501.DOI: 10.5246/jcps.2016.07.054

抗耐药长春瑞滨脂质体及其抗耐药性乳腺癌的效应与机制研究

谢红军, 刘磊, 曾凡, 沐黎敏, 赵曜, 阎妍, 胡英杰, 吴佳栓, 卜英子, 张婧莹, 吕万良^*

北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2016-03-27 修回日期:2016-04-15 出版日期:2016-07-19 发布日期:2016-04-02
通讯作者: Tel./Fax: +86-010-82802683, E-mail: luwl@bjmu.edu.cn
基金资助:
Key Grant of Beijing Natural Science Foundation (Grant No. 7131009), and the National Science Foundation of China (Grant No. 81373343).

Efficacy and mechanism of antiresistant vinorelbine liposomes in treating resistant breast cancer cells

Hongjun Xie, Lei Liu, Fan Zeng, Limin Mu, Yao Zhao, Yan Yan, Yingjie Hu, Jiashuan Wu, Yingzi Bu, Jingying Zhang, Wanliang Lu^*

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2016-03-27 Revised:2016-04-15 Online:2016-07-19 Published:2016-04-02
Contact: Tel./Fax: +86-010-82802683, E-mail: luwl@bjmu.edu.cn
Supported by:
Key Grant of Beijing Natural Science Foundation (Grant No. 7131009), and the National Science Foundation of China (Grant No. 81373343).

摘要/Abstract

摘要：

在乳腺癌的综合治疗策略中, 化疗药物对于清除癌细胞起关键作用。但是, 抗癌药物的多药耐药性是化疗成功的主要障碍之一。本研究旨在构建一种抗耐药长春瑞滨脂质体并考察其抗耐药性乳腺癌的效应与机制。以耐药性人乳腺癌MCF-7/adr细胞为模型进行效应和机制研究; 将长春瑞滨包封于脂质体内核、将他莫昔芬和地喹氯铵修饰脂质体表面, 制备了抗耐药长春瑞滨脂质体, 其平均粒径约100 nm。该脂质体表现出较强的体外杀伤耐药性乳腺癌效果, 其作用机制与如下因素有关: 增加耐药性癌细胞中药物摄取; 降低耐药性癌细胞膜转运蛋白ABCB1和ABCC10的表达; 载药脂质体靶向性作用于线粒体并诱导癌细胞凋亡。诱导凋亡信号通路包括: 激活凋亡酶caspase (8, 9, 3); 诱导线粒体释放细胞色素c; 激活Bax活性并抑制Mcl-1活性; 诱导产生活性氧ROS。因此, 本研究构建了一种新的抗耐药长春瑞滨脂质体, 可望用于耐药性乳腺癌的治疗, 并为耐药性乳腺癌的治疗提供一种备选策略。

关键词: 抗耐药长春瑞滨脂质体, 线粒体靶向, 凋亡信号通路, 疗效, 耐药性乳腺

Abstract:

Among the comprehensive treatment strategies of breast cancer, chemotherapy plays a crucial role in eliminating cancer cells. However, multidrug resistance is one of the major obstacles to successful treatment. The objectives of this study were to construct an antiresistant vinorelbine liposomes and to demonstrate the efficacy and mechanism for treating resistant breast cancer cells. The study was performed using breast cancer MCF-7/adr cells. The antiresistant vinorelbine liposomes were modified with tamoxifen and dequalinium. The average particle size of antiresistant vinorelbine liposomes were approximately 100 nm, and they showed a robust overall anticancer efficacy by direct killing and by apoptosis induction. The mechanisms were associated with increased cellular uptake, decreased ABCB1 and ABCC10 transporters, and targeting to mitochondria. The apoptosis signaling pathways were ralated to activiated caspases (8, 9, 3), induced release of cytochrome c from mitochondria, activated Bax, inhibited Mcl-1, and generation of ROS. The new antiresistant vinorelbine liposomes could be a useful formulation deserving further development, and the present study provides a potential strategy for circumventing drug resistance in breast cancer.

Key words: Antiresistant vinorelbine liposomes, Mitochondrial targeting, Apoptosis signaling pathways, Efficacy, Resistant breast cancer

中图分类号:

R943

Supporting:

谢红军, 刘磊, 曾凡, 沐黎敏, 赵曜, 阎妍, 胡英杰, 吴佳栓, 卜英子, 张婧莹, 吕万良. 抗耐药长春瑞滨脂质体及其抗耐药性乳腺癌的效应与机制研究[J]. 中国药学(英文版), 2016, 25(7): 489-501.

Hongjun Xie, Lei Liu, Fan Zeng, Limin Mu, Yao Zhao, Yan Yan, Yingjie Hu, Jiashuan Wu, Yingzi Bu, Jingying Zhang, Wanliang Lu. Efficacy and mechanism of antiresistant vinorelbine liposomes in treating resistant breast cancer cells[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(7): 489-501.

参考文献

[1] He, X.; Wang, L.; Li, W.; Yu, Z.; Wang, X. Int. J. Clin. Exp. Med. 2015, 8, 21925-21931.
[2] Thariat, J.; Kirova, Y.; Milano, G.; Mornex, F. Cancer Radiother. 2014, 18, 270-279.
[3] Pusztai, L.; Karn, T.; Safonov, A.; Abu-Khalaf, M.M.; Bianchini, G. Clin. Cancer Res. 2016, Feb 11 [Epub ahead of print].
[4] van der Hage, J.A.; Putter, H.; Bonnema J., Bartelink, H.; Therasse, P.; van de Velde, C.J. Eur. J. Cancer. 2003, 39, 2192-2199.
[5] ter Beek, J.; Guskov, A.; Slotboom, D.J. J. Gen. Physiol. 2014, 143, 419-435.
[6] Synold, T.W.; Dussault, I.; Forman, B.M. Nature Med. 2001, 7, 584-590.
[7] Shen, D.W.; Goldenberg, S.; Pastan, I.; Gottesman, M.M. J. Cell Physiol. 2000, 183, 108-116.
[8] Barth, B.M.; Cabot, M.C.; Kester, M. Anticancer Agents Med. Chem. 2011, 11, 911-919.
[9] Sun, W.L.; Lan, D.; Gan, T.Q.; Cai, Z.W. Neoplasma. 2015, 62, 199-208.
[10] Harris, A.L.; Hochhause, D. Acta Oncolog. 1992, 31, 205-213.
[11] Jones, A.; O'Brien, M.; Sommer, H.; Nowara, E.; Welt, A.; Pienkowski, T.; Rolski, J.; Pham, M.L.; Perraud, K.; Trillet-Lenoir, V. Cancer Chemother. Pharmacol. 2010, 65, 755-763.
[12] Xu, M.; Jiang, D.; Shen, J.; Zheng, H.; Fan, W. Oncol. Rep. 2016 Jan 15 [Epub ahead of print].
[13] Gregory, R.K.; Smith, I.E. Br. J. Cancer. 2000, 82, 1907-1913.
[14] Jordan, V.C. Br. J. Pharmacol. 2006, 147, S269-276.
[15] Mao, Z.; Zhou, J.; Luan, J.; Sheng, W.; Shen, X.; Dong, X. Biomed. Pharmacother. 2014, 68, 179-183.
[16] Li, X.T.; Ju, R.J.; Li, X.Y.; Zeng, F.; Shi, J.F.; Liu, L.; Zhang, C.X.; Sun, M.G.; Lou, J.N.; Lu, W.L. Oncotarget. 2014, 5, 6497-6511.
[17] Modica-Napolitano, J.S.; Aprille, J.R. Adv. Drug. Deliv. Rev. 2001, 49, 63-70.
[18] Weissig, V.; Torchilin, V.P. J. Drug Target. 2001, 9, 1-13.
[19] Sadoqi, M.; Lau-Cam, C.A.; Wu, S.H. J. Colloid. Interface Sci. 2009, 333, 585-589.
[20] Zhang, Z.; Tan, S.; Feng, S.S. Biomaterials, 2012, 33, 4889-4906.
[21] Cao, N.; Feng, S.S. Biomaterials, 2008, 29, 3856-3865.
[22] Yao, H.J.; Ju, R.J.; Wang, X.X.; Zhang, Y.; Li, R.J.; Yu, Y.; Zhang, L.; Lu, W.L. Biomaterials. 2011, 32, 3285-3302.
[23] Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. Adv. Drug Deliv. Rev. 2015 Oct 9 [Epub ahead of print].
[24] Ju, R.J.; Li, X.T.; Shi, J.F.; Li, X.Y.; Sun, M.G.; Zeng, F.; Zhou, J.; Liu, L.; Zhang, C.X.; Zhao, W.Y.; Lu, W.L. Biomaterials. 2014, 35, 7610-7621.
[25] Podduturi, V.P.; Magaña, I.B.; O'Neal, D.P.; Derosa, P.A. Comput. Methods Programs Biomed. 2013, 112, 58-68.
[26] Wang, X.X.; Li, Y.B.; Yao, H.J.; Ju, R.J.; Zhang, Y.; Li, R.J.; Yu, Y.; Zhang, L.; Lu, W.L. Biomaterials. 2011, 32, 5673-5687.
[27] Li, N.; Zhang, C.X.; Wang, X.X.; Zhang, L.; Ma, X.; Zhou, J.; Ju, R.J.; Li, X.Y.; Zhao, W.Y.; Lu, W.L. Biomaterials. 2013, 34, 3366-3380.
[28] Abraham, J.; Edgerly, M.; Wilson, R.; Chen, C.; Rutt, A.; Bakke, S.; Robey, R.; Dwyer, A.; Goldspiel, B.; Balis, F.; Van Tellingen, O.; Bates, S.E.; Fojo, T. Clin. Cancer Res. 2009, 15, 3574-3582.
[29] Keppler, D. Handb. Exp. Pharmacol. 2011, 201, 299-323.
[30] Domanitskaya, N.; Wangari-Talbot, J.; Jacobs, J.; Peiffer, E.; Mahdaviyeh, Y.; Paulose, C.; Malofeeva, E.; Foster, K.; Cai, K.Q.; Zhou, Y.; Egleston, B.; Hopper-Borge, E. Br. J. Cancer. 2014, 111, 696-707.
[31] Yamada, Y.; Akita, H.; Kogure, K.; Kamiya, H.; Harashima, H. Mitochondrion. 2007, 7, 63-71.
[32] Weiss, M.J.; Wong, J.R.; Ha, C.S.; Bleday, R.; Salem, R.R.; Steele, G.D.Jr.; Chen, L.B. Proc. Natl. Acad. Sci. USA. 1987, 84, 5444-5448.
[33] Zhou, J.; Zhao, W.Y.; Ma, X.; Ju, R.J.; Li, X.Y.; Li, N.; Sun, M.G.; Shi, J.F.; Zhang, C.X.; Lu, W.L. Biomaterials. 2013, 34, 3626-3638.
[34] Makowska, K.; Estan, M.C.; Ganan-Gomez, I.; Boyano-Adanez, M.C.; Garcia-Perez, A.I.; Sancho, P. Mol. Biol. (Mosk). 2014, 48, 416-428.
[35] Zhang, Y.; Li, R.J.; Ying, X.; Tian, W.; Yao, H.J.; Men, Y.; Yu, Y.; Zhang, L.; Ju, R.J.; Wang, X.X.; Zhou, J.; Chen, J.X.; Li, N.; Lu, W.L. Mol. Pharm. 2011, 8, 162-175.
[36] Potten, C.S.; Wilson, J. Apoptosis. Cambridge: Cambridge University Press, 2004.
[37] Green, D.R. Cell. 2000, 102, 1-4.
[38] Riedl, S.J.; Shi, Y. Nat. Rev. Mol. Cell. Biol. 2004, 5, 897-907.
[39] Li, X.; Ruan, G.R.; Lu, W.L.; Hong, H.Y.; Liang, G.W.; Zhang, Y.T.; Liu, Y.; Long, C.; Ma, X.; Yuan, L.; Wang, J.C.; Zhang, X.; Zhang, Q. J. Control. Release. 2006, 112, 186-198.

抗耐药长春瑞滨脂质体及其抗耐药性乳腺癌的效应与机制研究

Efficacy and mechanism of antiresistant vinorelbine liposomes in treating resistant breast cancer cells

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 14

编辑推荐

Metrics

本文评价

[1]	杨晗春, 成斐, 黄娟娟. 艾曲波帕对难治性原发免疫性血小板减少症的疗效及其对细胞免疫功能的影响[J]. 中国药学(英文版), 2023, 32(9): 736-743.
[2]	朱愿超, 陈晨, 胡欣. 比阿培南在高龄老年患者中的应用[J]. 中国药学(英文版), 2023, 32(2): 145-152.
[3]	袁叶, 李亚男, 赵晴, 于博, 杨秀岭. 基于PK/PD模型和蒙特卡洛模拟评价头孢曲松给药方案[J]. 中国药学(英文版), 2022, 31(5): 382-388.
[4]	李春杏, 朱元明, 刘桦, 徐钊. 促动力药联合质子泵抑制剂与单独质子泵抑制剂治疗胃食管反流疾病疗效的荟萃分析[J]. 中国药学(英文版), 2021, 30(4): 347-356.
[5]	周艳, 宋恒文, 邵志超, 尹博民, 付西美, 谢典佑, 韦利军. 一种新的细胞周期蛋白依赖性激酶(CDK)9抑制剂QHRD107对急性髓系白血病的临床前疗效[J]. 中国药学(英文版), 2021, 30(2): 146-156.
[6]	陈倩, 赵旭阳, 宋宇靖, 李少一, 雷婉钰, 马维宁, 黄卓. 鉴定用于评估切除性癫痫手术后癫痫发作情况的血清生物标志物[J]. 中国药学(英文版), 2020, 29(8): 528-541.
[7]	杨东升, 马玲云, 牛剑钊, 许鸣镝. 美国授权仿制药应用简介[J]. 中国药学(英文版), 2019, 28(6): 439-445.
[8]	杨东升, 马玲云, 牛剑钊, 许鸣镝. 美国国家药品编码应用简介[J]. 中国药学(英文版), 2019, 28(3): 203-208.
[9]	牛剑钊, 杨东升, 许鸣镝. 欧盟仿制药参比制剂检索与确认简介[J]. 中国药学(英文版), 2018, 27(11): 805-812.
[10]	林志燕, 田怀平, 李方, 秦丽萍, 张欣, 陆晓彤. 舒肝祛脂胶囊治疗成人单纯性肥胖的临床疗效及安全性评价[J]. 中国药学(英文版), 2017, 26(12): 890-894.
[11]	刘磊, 居瑞军, 谢红军, 曾凡, 张诚翔, 赵炜煜, 吕万良. 复方表阿霉素奎宁注射剂对耐药乳腺癌的治疗效应与机制研究[J]. 中国药学(英文版), 2015, 24(9): 563-571.
[12]	罗晓, 邵宏. 伊曲康唑治疗EICU侵袭性真菌感染的疗效与安全性分析[J]. 中国药学(英文版), 2015, 24(10): 678-682.
[13]	石继凤, 居瑞军, 孙梦舸, 李秀英, 赵曜, 曾凡, 吕万良. 培美曲塞-磷脂偶联物修饰的靶向性舒尼替尼与长春瑞滨脂质体的研制及其在体外对耐药性乳腺癌的抑制效应[J]. 中国药学(英文版), 2014, 23(5): 287-294.
[14]	范超, 李馨儒, 周艳霞, 赵勇, 李文静, 马淑金, 刘艳^*, 李桂玲, 李眉. 粉防已碱纳米醇质体的制备、表征和抗关节炎疗效[J]. , 2012, 21(4): 311-320.