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
Corresponding AuthorPopanda, O (reprint author), German Canc Res Ctr, Div Epigen & Canc Risk Factors, Neuenheimer Feld 280, D-69120 Heidelberg, Germany, o.popanda@dkfz.de
2012-03-15
Source PublicationTOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN0041-008X
Volume259Issue:3Pages:302-310
AbstractTargeting 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.
KeywordCancer Therapy Synthetic Lethal Traditional Chinese Medicine Xpc Ercc6 Csb
Subject AreaPharmacology & Pharmacy ; Toxicology
DOI10.1016/j.taap.2012.01.006
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS SubjectPharmacology & Pharmacy ; Toxicology
WOS IDWOS:000301892800005
Citation statistics
Cited Times:10[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/10357
Collection植物化学与西部植物资源持续利用国家重点实验室
Affiliation1.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
Recommended Citation
GB/T 7714
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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