c9, t11-CLA­PTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用

doi:R965, R943

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (11): 751-759.DOI: R965, R943

c9, t11-CLAPTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用

杨科¹, 李星火¹, 李丹¹, 柯曦宇¹, 张烜^1*, 张强^1,2

1. 北京大学医学部药学院药剂学系, 北京 100191
2. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2014-05-23 修回日期:2014-05-28 出版日期:2014-11-24 发布日期:2014-06-09
通讯作者: Tel./Fax: 86-10-82805928,
基金资助:
National Natural Science Foundation of China (Grant No. 81172992) and the National Basic Research Program of China (973 Program, Grant No. 2013CB932501) and Innovation Team of Ministry of Education (Grant No. BMU20110263).

The anti-tumor efficacy of c9, t11-CLA-PTX and t10, c12-CLA-PTX on MCF-7 breast cancer cells: in vitro and in vivo

Ke Yang¹, Xinghuo Li¹, Dan Li¹, Xiyu Ke¹, Xuan Zhang^1*, Qiang Zhang^1,2

1. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2014-05-23 Revised:2014-05-28 Online:2014-11-24 Published:2014-06-09
Contact: Tel./Fax: 86-10-82805928,
Supported by:
National Natural Science Foundation of China (Grant No. 81172992) and the National Basic Research Program of China (973 Program, Grant No. 2013CB932501) and Innovation Team of Ministry of Education (Grant No. BMU20110263).

摘要/Abstract

摘要：

在前期研究中, CLA-mixture-PTX展现出了对黑色素瘤与脑胶质瘤一定的抗肿瘤作用。本研究旨在探索c9, t11-CLAPTX与t10, c12-CLA-PTX对人源乳腺癌MCF-7细胞的体内外抗肿瘤作用。研究中考察了c9, t11-CLAPTX与t10, c12-CLA-PTX的体外细胞摄取、细胞毒、细胞凋亡,以及细胞周期作用。用荷瘤BALB/c裸鼠研究了c9, t11-CLAPTX与t10, c12-CLA-PTX的体内抗肿瘤作用。体外细胞毒研究结果表明: t10, c12-CLA-PTX的IC₅₀为(0.17±0.02) µM, 显著优于CLA-mixture-PTX (1.08±0.15) µM (P<0.01), 后者显著优于c9, t11-CLAPTX (6.50±1.20) µM (P<0.01)。与空白对照组相比, c9, t11-CLAPTX与t10, c12-CLA-PTX均可使细胞总凋亡比例增加 (P<0.01); 和CLA-mixture-PTX组相比, t10, c12-CLA-PTX可使细胞总凋亡比例增加(P<0.01), c9, t11-CLAPTX则使细胞总凋亡比例降低(P<0.01)。与空白对照组相比, c9, t11-CLAPTX与t10, c12-CLA-PTX均将细胞周期阻滞于S期与G₂-M, 与CLA-mixture-PTX相同。t10, c12-CLA-PTX的细胞摄取量显著高于CLA-mixture-PTX (P<0.01), 后者的细胞摄取量显著高于c9, t11-CLAPTX (P<0.01)。体内抗肿瘤药效研究结果显示,t10, c12-CLA-PTX的抗肿瘤活性显著高于空白对照组和CLA-mixture-PTX组(P<0.01), 而c9, t11-CLAPTX的抗肿瘤活性仅高于空白对照组(P<0.01)。上述结果表明, t10, c12-CLA-PTX对MCF-7细胞有显著体内外抗肿瘤作用, 可以作为CLA-mixture-PTX的替代药物进行后续研究。

关键词: c9,t11-CLAPTX, t10,c12-CLA-PTX, 凋亡, 细胞周期, 细胞摄取, 抗肿瘤作用

Abstract:

Considering the results of our previous research that conjugated linoleic acid mixture-paclitaxel (CLA-mixture-PTX) possesses anti-tumor activity against melanoma and brain glioma, the purpose of this study was to investigate the potential anti-tumorefficacy of cis-9, trans-11-conjugated linoleic acidpaclitaxel (c9, t11-CLA-PTX) and trans-10, cis-12-conjugated linoleic acidpaclitaxel (t10, c12-CLA-PTX) on MCF-7 breast cancer cell line in vitro and in vivo. The in vitro cytotoxicity, apoptosis induction effect and cell cycle arresting effect of c9, t11-CLA-PTX and t10, c12-CLA-PTX were investigated. The in vitro cellularuptake of c9, t11-CLA-PTX and t10, c12-CLA-PTX in MCF-7 cells were also analyzed. Besides, the anti-tumor activity of c9, t11-CLA-PTX and t10, c12-CLA-PTX was evaluated in MCF-7 tumor bearing nude mice in vivo. The in vitro cytotoxicityresults showed that the value of IC₅₀ of the t10, c12-CLA-PTX is (0.17±0.02) µM, compared with that of (1.08±0.15) µM in CLA-mixture-PTX and (6.50±1.20) µM in c9, t11-CLAPTX treatment group (P<0.01). Both t10, c12-CLA-PTX and c9, t11-CLAPTX increased the percentage of total apoptotic cells compared with that of control (P<0.01). And the rank of apoptosis induction efficacy was t10, c12-CLA-PTX>CLA-mixture-PTX>c9, t11-CLAPTX (P<0.01). Compared with untreated cells, the t10, c12-CLA-PTX and c9, t11-CLAPTX arrested cell cycle progression at the S and G₂–M phase. The amount of cellular uptake of t10, c12-CLA-PTX was significantly higher than that of CLA-mixture-PTX (P<0.01), which was significantly higherthan that of c9, t11-CLAPTX (P<0.01). The rank of in vivo anti-tumor activity was t10, c12-CLA-PTX>CLA-mixture-PTX> c9, t11-CLAPTX (P<0.01). In conclusion, our study demonstrated that both t10, c12-CLA-PTX and c9, t11-CLAPTX has significant anti-tumor activity in MCF-7 cell line. And while c9, t11-CLAPTX showed weaker inhibitory effect than CLA-mixture-PTX, stronger inhibitory effect was presented by t10, c12-CLA-PTX, which could be a promising alternative for CLA-mixture-PTX.

Key words: c9,t11-CLAPTX, t10,c12-CLA-PTX, Apoptosis, Cell cycle, Cellular uptake, Anti-tumor efficacy

中图分类号:

10.5246/jcps.2014.11.095

Supporting:

杨科, 李星火, 李丹, 柯曦宇, 张烜, 张强. c9, t11-CLAPTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用[J]. 中国药学(英文版), 2014, 23(11): 751-759.

Ke Yang, Xinghuo Li, Dan Li, Xiyu Ke, Xuan Zhang, Qiang Zhang. The anti-tumor efficacy of c9, t11-CLA-PTX and t10, c12-CLA-PTX on MCF-7 breast cancer cells: in vitro and in vivo[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(11): 751-759.

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c9, t11-CLAPTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用

The anti-tumor efficacy of c9, t11-CLA-PTX and t10, c12-CLA-PTX on MCF-7 breast cancer cells: in vitro and in vivo

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c9, t11-CLA­PTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用

The anti-tumor efficacy of c9, t11-CLA-PTX and t10, c12-CLA-PTX on MCF-7 breast cancer cells: in vitro and in vivo

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c9, t11-CLAPTX与t10, c12-CLA-PTX对MCF-7细胞的体内外抗肿瘤作用