DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences

Velliyur Viswesh, Allison M. Hays, Kent Gates, Daekyu Sun

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The natural product leinamycin has been found to produce abasic sites in duplex DNA through the hydrolysis of the glycosidic bond of guanine residues modified by this drug. In the present study, using a synthetic oligonucleotide duplex, we demonstrate spontaneous DNA strand cleavage at leinamycin-induced abasic sites through a β-elimination reaction. However, methoxyamine modification of leinamycin-induced abasic sites was found to be refractory to the spontaneous β-elimination reaction. Furthermore, this complex was even resistant to the δ-elimination reaction with hot piperidine treatment. Bleomycin and methyl methanesulfonate also induced strand cleavage in a synthetic oligonucleotide duplex even without thermal treatment. However, methoxyamine has a negligible effect on DNA strand cleavage induced by both drugs, suggesting that the mechanism of DNA cleavage induced by leinamycin might be different from those induced by bleomycin or methyl methanesulfonate. In this study, we also assessed the cytotoxicity of leinamycin against a collection of mammalian cell lines defective in various repair pathways. The mammalian cell line defective in the nucleotide excision repair (NER) or base excision repair (BER) pathways was about 3 to 5 times more sensitive to leinamycin as compared to the parental cell line. In contrast, the radiosensitive mutant xrs-5 cell line deficient in V(D)J recombination showed similar sensitivity towards leinamycin compared to the parental cell line. Collectively, our findings suggest that both NER and BER pathways play an important role in the repair of DNA damage caused by leinamycin.

Original languageEnglish (US)
Pages (from-to)4413-4421
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2012

Fingerprint

DNA Cleavage
Anti-Bacterial Agents
Repair
DNA
DNA Repair
Cells
Cell Line
Methyl Methanesulfonate
Bleomycin
Oligonucleotides
Nucleotides
Drug Residues
V(D)J Recombination
leinamycin
Guanine
Cytotoxicity
Biological Products
Pharmaceutical Preparations
Refractory materials
DNA Damage

Keywords

  • Abasic site
  • DNA repair
  • DNA strand breaks
  • Leinamycin

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences. / Viswesh, Velliyur; Hays, Allison M.; Gates, Kent; Sun, Daekyu.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 14, 15.07.2012, p. 4413-4421.

Research output: Contribution to journalArticle

Viswesh, Velliyur ; Hays, Allison M. ; Gates, Kent ; Sun, Daekyu. / DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 14. pp. 4413-4421.
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