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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

21卷

期数:

2015年04期

页码:

277-281

栏目:

基础医学

出版日期:

2015-07-15

文章信息/Info

Title:

Effects of new alkylating agent temozolomide easter on the proliferation of glioma cells

文章编号:

1006-8147（2015）04-0277-05

作者:

郭珊珊¹; 朱仲玲¹; 徐 辉¹; 丁凤霞¹; 王国成²; 赵 敏²; 阎 昭¹

 

(1.天津医科大学肿瘤医院肿瘤研究所，国家药物临床试验机构，国家肿瘤临床医学研究中心，天津市“肿瘤防治”重点实验室，天津 300060；2.天津天士力集团研究院，天津300402)

Author(s):

GUO Shan-shan¹;  ZHU Zhong-ling¹;  XU Hui¹;  DING Feng-xia¹;  WANG Guo-cheng²;  ZHAO Min²;  YAN Zhao^1*

（1. Department of Clinical Pharmacology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China； 2.China Tasly R&D Institute, Tianjin Tasly Group Co., Tianjin 300402, China)

关键词:

替莫唑胺酯; 多形性脑胶质瘤; 细胞凋亡; O⁶-甲基鸟嘌呤-甲基转移酶

Keywords:

temozolomide easter;  glioma;  apoptosis;  O⁶-methylguanine methyltransferase

分类号:

R739.4

DOI:

-

文献标志码:

A

摘要:

目的 : 以替莫唑胺（TMZ）为阳性对照，研究新烷化剂替莫唑胺酯（TMZ-HE）在体外抑制脑胶质瘤LN-18细胞生长并诱导其凋亡的作用。方法： MTT比色法比较相同浓度梯度的TMZ和TMZ-HE作用后对LN-18细胞增殖的影响；二维克隆法观察TMZ、TMZ-HE长期作用的效果；流式细胞仪检测细胞凋亡率；Hoechst33342/PI荧光染色观察细胞核形态改变及细胞坏死情况；Western Blot检测TMZ和TMZ-HE对LN-18细胞内耐药蛋白MGMT的影响。结果：TMZ-HE较TMZ明显抑制LN-18细胞的生长和增殖，呈浓度及时间依赖性反应; TMZ-HE的长期作用效果同样优于TMZ；TMZ-HE诱导LN-18细胞发生凋亡率高于TMZ；TMZ-HE能够更早消耗耐药蛋白MGMT。结论：TMZ-HE较TMZ更早更多地消耗耐药蛋白，增加TMZ-HE对胶质瘤LN-18细胞的增殖抑制及诱导凋亡作用。

Abstract:

Objective: To investigate the effect of temozolomide easter (TMZ-HE) on the proliferation and apoptosis of glioma LN-18 cells in vitro compared with temozolomide (TMZ). Methods: Methyl thiazolyl tetrazolium (MTT) assay was used to measure the effects on the proliferation of LN-18 cells cultured with graded concentrations of TMZ and TMZ-HE for 24, 48, 72 and 96 h. The long term effect was measured by colony formation assay. Hoechst 33342 and PI fluorescence staining were used to observe the cellular morphological changes and cell necrosis. The AnnexinV-fluoresce in isothiocyanate (FITC) and propidium iodide (PI) assay by flow cytometer were applied to detect the apoptosis induced by TMZ and TMZ-HE. Expression of resistant protein MGMT in LN-18 after treatment with TMZ and TMZ-HE was detected by Western blot. Results: The proliferation of LN-18 cells was significantly suppressed by TMZ-HE in a concentration-and time-dependent manner compared with TMZ. More cellular apoptosis of the LN-18 cells was induced in a concentration-dependent manner. TMZ-HE could block the expressing of MGMT in LN-18 earlier than TMZ. Conclusion: TMZ-HE could inhibit proliferation and induce apoptosis by blocked resistant protein MGMT in LN-18 cells. These effects are much stronger than TMZ.

参考文献/References:

[1]Wen P Y, Kesari S. Malignant gliomas in adults[J].N Engl J Med,2008,359(5):492
[2]Helseth R, Helseth E, Johannesen T B, et al. Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme[J].Acta Neurol Scand,2010,122(3):159
[3]Zhang J, Stevens M F, Bradshaw T D. Temozolomide: mechanisms of action, repair and resistance[J].Curr Mol Pharmacol,2012,5(1):102
[4]Roos W P, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis[J].Cancer Lett,2013,332(2):237
[5]Silber J R, Bobola M S, Blank A, et al. O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems[J].Biochim Biophys Acta,2012,1826(1):71
[6]Spiegl-Kreinecker S, Pirker C, Filipits M, et al. O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients[J].Neuro Oncol,2010,12(1):28
[7]Inno A, Fanetti G, Di Bartolomeo M, et al. Role of MGMT as biomarker in colorectal cancer[J].World J Clin Cases,2014,2(12):835
[8]Suppasansatorn P, Wang G, Conway B R, et al. Skin delivery potency and antitumor activities of temozolomide ester prodrugs[J].Cancer Lett,2006,244(1):42
[9]Happold C, Roth P, Wick W, et al. Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells[J].J Neurochem,2012,122(2):444
[10]Fan C H, Liu W L, Cao H, et al. O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas[J].Cell Death Dis,2013,4:e876
[11]Dolecek T A, Propp J M, Stroup N E, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009[J].Neuro Oncol,2012,14(Suppl 5):1
[12]Stupp R, Hegi M E, van den Bent M J, et al. Changing paradigms--an update on the multidisciplinary management of malignant glioma[J].Oncologist,2006,11(2):165
[13]Cavaliere R, Wen P Y, Schiff D. Novel therapies for malignant gliomas[J].Neurol Clin,2007,25(4):1141
[14]Wiewrodt D, Nagel G, Dreimüller N, et al. MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome[J].Int J Cancer,2008,122(6):1391
[15]Ramirez Y P, Weatherbee J L, Wheelhouse R T, et al. Glioblastoma multiforme therapy and mechanisms of resistance[J].Pharmaceuticals (Basel),2013,6(12):1475
[16]Huang H, Lin H, Zhang X, et al. Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-κB-dependent pathway[J].Oncol Rep,2012,27(6):2050
[17]Roos W P, Batista L F, Naumann S C, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine[J].Oncogene,2007,26(2):186
[18]Goldstein M, Roos W P, Kaina B. Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: contribution of DNA replication, transcription inhibition and Chk/p53 signaling[J].Toxicol Appl Pharmacol,2008,229(1):20
[19]Zou Y, Wang Q, Li B, et al. Temozolomide induces autophagy via ATM?AMPK?ULK1 pathways in glioma[J].Mol Med Rep,2014,10(1):411
[20]Zanotto-Filho A, Braganhol E, Klafke K, et al. Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas[J].Cancer Lett,2015,358(2):220

相似文献/References:

备注/Memo

备注/Memo:

基金项目 十二五“重大新药创制”科技重大专项课题基金资助项目（2013ZX09303001）

作者简介 郭珊珊（1988-），女，硕士在读，研究方向：肿瘤临床药理学；通信作者：阎昭，E-mail: yanzhaopaper@163.com。

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更新日期/Last Update: 2015-07-16