Header

UZH-Logo

Maintenance Infos

Modulation of cytotoxicity by transcription-coupled nucleotide excision repair is independent of the requirement for bioactivation of acylfulvene


Otto, Claudia; Spivak, Graciela; Aloisi, Claudia M.N; Menigatti, Mirco; Naegeli, Hanspeter; Hanawalt, Philip C; Tanasova, Marina; Sturla, Shana J (2017). Modulation of cytotoxicity by transcription-coupled nucleotide excision repair is independent of the requirement for bioactivation of acylfulvene. Chemical Research in Toxicology, 30(3):769-776.

Abstract

Bioactivation as well as DNA repair affects the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative Contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents We evaluated the influence of cellular. ioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent acylfulvene (AF). We compared the cytotoxicity and RNA synthesis inhibition by AF and its synthetiC activated analogue iso-MO in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GQ-NER): We related these data to the inherent bioactivation capacity of each cell type on the basis of mRNA levels. We demonstrated that specific inactivation of TC-NER by siRNA had the largest positive impact on AF activity in a cancer cell line. These findings establish that transcription coupled DNA repair reduces cellular sensitivity to AF, independent of the requirement for bioactivation.

Abstract

Bioactivation as well as DNA repair affects the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative Contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents We evaluated the influence of cellular. ioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent acylfulvene (AF). We compared the cytotoxicity and RNA synthesis inhibition by AF and its synthetiC activated analogue iso-MO in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GQ-NER): We related these data to the inherent bioactivation capacity of each cell type on the basis of mRNA levels. We demonstrated that specific inactivation of TC-NER by siRNA had the largest positive impact on AF activity in a cancer cell line. These findings establish that transcription coupled DNA repair reduces cellular sensitivity to AF, independent of the requirement for bioactivation.

Statistics

Citations

Dimensions.ai Metrics
2 citations in Web of Science®
3 citations in Scopus®
3 citations in Microsoft Academic
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 28 Jan 2018
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research

05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:March 2017
Deposited On:28 Jan 2018 16:53
Last Modified:19 Aug 2018 12:37
Publisher:American Chemical Society (ACS)
ISSN:0893-228X
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.chemrestox.6b00240
PubMed ID:28076683
Project Information:
  • : FunderFP7
  • : Grant ID260341
  • : Project TitleDNA-AMP - DNA Adduct Molecular Probes: Elucidating the Diet-Cancer Connection at Chemical Resolution
  • : FunderSNSF
  • : Grant ID31003A_156280
  • : Project TitleDNA Alkylation and Resistance in Antitumor Drug Toxicity

Download