The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells
Abbasi, Rashda1; Efferth, Thomas2; Kuhmann, Christine1; Opatz, Till3; Hao, Xiaojiang4; Popanda, Odilia1; Schmezer, Peter1
2012-03-15
发表期刊TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN0041-008X
卷号259期号:3页码:302-310
摘要Targeting synthetic lethality in DNA repair pathways has become a promising anti-cancer strategy. However little is known about such interactions with regard to the nucleotide excision repair (NER) pathway. Therefore, cell lines with a defect in the NER genes ERCC6 or XPC and their normal counterparts were screened with 53 chemically defined phytochemicals isolated from plants used in traditional Chinese medicine for differential cytotoxic effects. The screening revealed 12 drugs that killed NER-deficient cells more efficiently than proficient cells. Five drugs were further analyzed for IC50 values, effects on cell cycle distribution, and induction of DNA damage. Ascaridol was the most effective compound with a difference of >1000-fold in resistance between normal and NER-deficient cells (IC50 values for cells with deficiency in ERCC6: 0.15 mu M, XPC: 0.18 mu M, and normal cells: >180 mu M). NER-deficiency combined with ascaridol treatment led to G2/M-phase arrest, an increased percentage of subG1 cells, and a substantially higher DNA damage induction. These results were confirmed in a second set of NER-deficient and -proficient cell lines with isogenic background. Finally, ascaridol was characterized for its ability to generate oxidative DNA damage. The drug led to a dose-dependent increase in intracellular levels of reactive oxygen species at cytotoxic concentrations, but only NER-deficient cells showed a strongly induced amount of 8-oxodG sites. In summary, ascaridol is a cytotoxic and DNA-damaging compound which generates intracellular reactive oxidative intermediates and which selectively affects NER-deficient cells. This could provide a new therapeutic option to treat cancer cells with mutations in NER genes. (C) 2012 Elsevier Inc. All rights reserved.
关键词Cancer Therapy Synthetic Lethal Traditional Chinese Medicine Xpc Ercc6 Csb
资助信息Higher Education Commission (HEC) of Pakistan; Deutscher Akademischer Austauschdienst (DAAD)
学科领域Pharmacology & Pharmacy ; Toxicology
DOI10.1016/j.taap.2012.01.006
收录类别SCI
语种英语
WOS研究方向Pharmacology & Pharmacy ; Toxicology
WOS类目Pharmacology & Pharmacy ; Toxicology
WOS记录号WOS:000301892800005
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/10357
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.German Canc Res Ctr, Div Epigen & Canc Risk Factors, D-69120 Heidelberg, Germany
2.Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, D-55128 Mainz, Germany
3.Johannes Gutenberg Univ Mainz, Inst Organ Chem, D-55128 Mainz, Germany
4.Chinese Acad Sci, Kunming Inst Bot, Kunming 650204, Peoples R China
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Abbasi, Rashda,Efferth, Thomas,Kuhmann, Christine,et al. The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2012,259(3):302-310.
APA Abbasi, Rashda.,Efferth, Thomas.,Kuhmann, Christine.,Opatz, Till.,Hao, Xiaojiang.,...&Schmezer, Peter.(2012).The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells.TOXICOLOGY AND APPLIED PHARMACOLOGY,259(3),302-310.
MLA Abbasi, Rashda,et al."The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells".TOXICOLOGY AND APPLIED PHARMACOLOGY 259.3(2012):302-310.
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