环磷酰胺衍生物SLXM-2对小鼠肝癌H22细胞的DNA损伤作用

doi:10.5246/jcps.2014.01.002

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (1): 16-21.DOI: 10.5246/jcps.2014.01.002

环磷酰胺衍生物SLXM-2对小鼠肝癌H22细胞的DNA损伤作用

楚明明, 袁霞, 贾璇, 孙婷, 郭维, 蒋晓, 刘敬弢, 李润涛^*, 崔景荣^*

1. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2013-05-06 修回日期:2013-06-15 出版日期:2014-01-23 发布日期:2014-01-22
通讯作者: 李润涛*, 崔景荣*
基金资助:
Eleventh Five Year Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010).

DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H₂₂ cells in vivo

Mingming Chu, Xia Yuan, Xuan Jia, Ting Sun, Wei Guo, Xiao Jiang, Jingtao Liu, Runtao Li^*, Jingrong Cui^*

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

Received:2013-05-06 Revised:2013-06-15 Online:2014-01-23 Published:2014-01-22
Contact: Runtao Li*, Jingrong Cui*
Supported by:
Eleventh Five Year Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010).

摘要/Abstract

摘要：

化合物SLXM-2是一种环磷酰胺衍生物, 前期研究已经证实其具有良好的肿瘤抑制作用, 并具有较低的毒副作用。但是其作用机制尤其是对细胞DNA的损伤作用仍不清楚。本研究旨在评价SLXM-2对肝癌H₂₂腹水小鼠的生命延长作用与DNA损伤的关系, 并探讨可能的分子机制。实验结果证实, SLXM-2能够显著提高肝癌H₂₂腹水小鼠的生命延长率 (P<0.05)。进一步实验表明, SLXM-2能够造成肝癌H₂₂细胞DNA损伤, 显著上调γH2AX (Ser139), p-Chk1 (Ser296), p-Chk2 (Thr68), p-p53 (Ser15), p-p53 (Ser20)和p21的蛋白表达, 并显著下调p-ATR (Ser428)和p-ATM (Ser1981)的表达 (P<0.05)。总之, SLXM-2对肝癌H₂₂细胞具有显著的抑制作用, 分子机制与其能够造成肿瘤细胞DNA损伤有关。

关键词: SLXM-2, H22, DNA损伤, 单细胞凝胶电泳, DNA损伤相关蛋白

Abstract:

Compound SLXM-2, a derivative of cyclophosphamide (CTX), has shown potent growth-inhibitory effect on tumor cells with low toxicity in previous studies. However, the mechanism of its anti-tumor effect, especially on DNA damage, remains largely unclear. This study investigated the effect of SLXM-2 on the survival time of mice transplanted with the ascitic fluid-type hepatocarcinoma 22 (H₂₂). We also evaluated the correlation between DNA damaging effect of SLXM-2 and its anti-tumor effect, and to probe the possible molecular mechanism for its effect on H₂₂ cells. The results suggested that SLXM-2 significantly (P<0.05) prolonged the survival time of mice bearing the ascitic fluid-type H₂₂. Furthermore, SLXM-2 induced DNA damage in a dose-dependent manner in H₂₂ cells. Further investigation revealed that SLXM-2 significantly (P<0.05) up-regulated the expression levels of a series of DNA damage-related proteins, such as γH2AX (Ser139), p-Chk1 (Ser296), p-Chk2 (Thr68), p-p53 (Ser15), p-p53 (Ser20) and p21, and down-regulated the expression of p-ATR (Ser428) and p-ATM (Ser1981). In conclusion, SLXM-2 showed a remarkable anti-tumor activity on ascitic fluid-type H₂₂ cells, and its molecular mechanism is related to its DNA damaging effect.

Key words: SLXM-2, H22, DNA damage, SCGE, DNA damage-related proteins

中图分类号:

R962

Supporting: Eleventh Five Year Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010).

楚明明, 袁霞, 贾璇, 孙婷, 郭维, 蒋晓, 刘敬弢, 李润涛, 崔景荣. 环磷酰胺衍生物SLXM-2对小鼠肝癌H22细胞的DNA损伤作用[J]. 中国药学(英文版), 2014, 23(1): 16-21.

Mingming Chu, Xia Yuan, Xuan Jia, Ting Sun, Wei Guo, Xiao Jiang, Jingtao Liu, Runtao Li, Jingrong Cui. DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H₂₂ cells in vivo[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(1): 16-21.

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环磷酰胺衍生物SLXM-2对小鼠肝癌H22细胞的DNA损伤作用

DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H₂₂ cells in vivo

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环磷酰胺衍生物SLXM-2对小鼠肝癌H22细胞的DNA损伤作用

DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H22 cells in vivo

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DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H₂₂ cells in vivo