The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells

Publication type:
Journal article
Metadata:
Autoren
  • Rashda Abbasi
  • Thomas Efferth
  • Christine Kuhmann
  • Till Opatz
  • Xiaojiang Hao
  • Odilia Popanda
  • Peter Schmezer
Sammlungen
  • metadata
ISSN
0041-008X
Ausgabe der Veröffentlichung
3
Zeitschrift
Toxicology and applied pharmacology
Schlüsselwörter
  • 540 Chemie
  • 540 Chemistry and allied sciences
Sprache
eng
Paginierung
Seiten: 302 - 310
Datum der Veröffentlichung
2012
Herausgeber
Elsevier
Herausgeber URL
http://dx.doi.org/10.1016/j.taap.2012.01.006
Datum der Datenerfassung
2020
Datum, an dem der Datensatz öffentlich gemacht wurde
2020
Zugang
Public
Titel
The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells
Ausgabe der Zeitschrift
259

Data source: METADATA.UB

Other metadata sources:
Autoren
  • Rashda Abbasi
  • Thomas Efferth
  • Christine Kuhmann
  • Till Opatz
  • Xiaojiang Hao
  • Odilia Popanda
  • Peter Schmezer
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000301892800005&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.taap.2012.01.006
eISSN
1096-0333
Externe Identifier
  • Clarivate Analytics Document Solution ID: 913QP
  • PubMed Identifier: 22280988
ISSN
0041-008X
Ausgabe der Veröffentlichung
3
Zeitschrift
TOXICOLOGY AND APPLIED PHARMACOLOGY
Schlüsselwörter
  • Cancer therapy
  • Synthetic lethal
  • Traditional Chinese medicine
  • XPC
  • ERCC6
  • CSB
Paginierung
302 - 310
Datum der Veröffentlichung
2012
Status
Published
Titel
The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells
Sub types
  • Article
Ausgabe der Zeitschrift
259

Data source: Web of Science (Lite)

Autoren
  • Rashda Abbasi
  • Thomas Efferth
  • Christine Kuhmann
  • Till Opatz
  • Xiaojiang Hao
  • Odilia Popanda
  • Peter Schmezer
DOI
10.1016/j.taap.2012.01.006
ISSN
0041-008X
Ausgabe der Veröffentlichung
3
Zeitschrift
Toxicology and Applied Pharmacology
Sprache
en
Paginierung
302 - 310
Datum der Veröffentlichung
2012
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.taap.2012.01.006
Datum der Datenerfassung
2024
Titel
The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells
Ausgabe der Zeitschrift
259

Data source: Crossref

Abstract
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 IC(50) 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 (IC(50) values for cells with deficiency in ERCC6: 0.15μM, XPC: 0.18μM, and normal cells: >180μM). 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.
Addresses
  • Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Autoren
  • Rashda Abbasi
  • Thomas Efferth
  • Thomas Efferth
  • Christine Kuhmann
  • Till Opatz
  • Xiaojiang Hao
  • Odilia Popanda
  • Peter Schmezer
DOI
10.1016/j.taap.2012.01.006
eISSN
1096-0333
Externe Identifier
  • PubMed Identifier: 22280988
Open access
false
ISSN
0041-008X
Ausgabe der Veröffentlichung
3
Zeitschrift
Toxicology and applied pharmacology
Schlüsselwörter
  • Cell Line
  • Humans
  • DNA Damage
  • Peroxides
  • Reactive Oxygen Species
  • Monoterpenes
  • Drugs, Chinese Herbal
  • Antineoplastic Agents, Phytogenic
  • Medicine, Chinese Traditional
  • Inhibitory Concentration 50
  • DNA Repair
  • Dose-Response Relationship, Drug
  • M Phase Cell Cycle Checkpoints
  • G2 Phase Cell Cycle Checkpoints
  • Cyclohexane Monoterpenes
Sprache
eng
Medium
Print-Electronic
Online publication date
2012
Paginierung
302 - 310
Datum der Veröffentlichung
2012
Status
Published
Datum der Datenerfassung
2012
Titel
The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells.
Sub types
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
259

Data source: Europe PubMed Central

Abstract
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 IC(50) 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 (IC(50) values for cells with deficiency in ERCC6: 0.15μM, XPC: 0.18μM, and normal cells: >180μM). 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.
Date of acceptance
2012
Autoren
  • Rashda Abbasi
  • Thomas Efferth
  • Christine Kuhmann
  • Till Opatz
  • Xiaojiang Hao
  • Odilia Popanda
  • Peter Schmezer
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/22280988
DOI
10.1016/j.taap.2012.01.006
eISSN
1096-0333
Ausgabe der Veröffentlichung
3
Zeitschrift
Toxicol Appl Pharmacol
Schlüsselwörter
  • Antineoplastic Agents, Phytogenic
  • Cell Line
  • Cyclohexane Monoterpenes
  • DNA Damage
  • DNA Repair
  • Dose-Response Relationship, Drug
  • Drugs, Chinese Herbal
  • G2 Phase Cell Cycle Checkpoints
  • Humans
  • Inhibitory Concentration 50
  • M Phase Cell Cycle Checkpoints
  • Medicine, Chinese Traditional
  • Monoterpenes
  • Peroxides
  • Reactive Oxygen Species
Sprache
eng
Country
United States
Paginierung
302 - 310
PII
S0041-008X(12)00015-4
Datum der Veröffentlichung
2012
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2012
Titel
The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells.
Sub types
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
259

Data source: PubMed

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