ArticleChemical research in toxicology2010
Characterization of DNA damage induced by a natural product antitumor antibiotic leinamycin in human cancer cells.
Article in Chemical research in toxicology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 63 citations in OpenAlex.
- How nature incorporates sulfur and selenium into bioactive natural products.Current opinion in chemical biology · 2023Review
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- Estimation of the Level of Abasic Sites in Plant mRNA Using Aldehyde Reactive Probe.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Genome mining methods to discover bioactive natural products.Natural product reports · 2021Review
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- Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1.DNA repair · 2020Article
- A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives.Antibiotics (Basel, Switzerland) · 2020Review
- Targeting Bacterial Genomes for Natural Product Discovery.Trends in pharmacological sciences · 2020Review
- Targeting G-quadruplexes with Organic Dyes: Chelerythrine-DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy.Antioxidants (Basel, Switzerland) · 2019Article
- P450-Catalyzed Tailoring Steps in Leinamycin Biosynthesis Featuring Regio- and Stereoselective Hydroxylations and Substrate Promiscuities.Biochemistry · 2018Article
- Discovery of the leinamycin family of natural products by mining actinobacterial genomes.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Base excision repair of oxidative DNA damage: from mechanism to disease.Frontiers in bioscience (Landmark edition) · 2017Review
- Article
- Synthesis and evaluation of 8,4'-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin.Bioorganic & medicinal chemistry letters · 2015Article
- Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2'-deoxycytidine lesions.Nucleic acids research · 2014Article
- Quantitative detection of 8-Oxo-7,8-dihydro-2'-deoxyguanosine using chemical tagging and qPCR.Chemical research in toxicology · 2014Article
- Nucleosome core particle-catalyzed strand scission at abasic sites.Biochemistry · 2013Article
- On the formation and properties of interstrand DNA-DNA cross-links forged by reaction of an abasic site with the opposing guanine residue of 5'-CAp sequences in duplex DNA.Journal of the American Chemical Society · 2013Article
- Synthesis and characterization of a small analogue of the anticancer natural product leinamycin.Bioorganic & medicinal chemistry · 2013Article
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3 authors at 2 institutions in 1 country.
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Abstract
Leinamycin is a structurally novel Streptomyces-derived natural product that displays very potent activity against various human cancer cell lines (IC(50) values in the low nanomolar range). Previous in vitro biochemical studies have revealed that leinamycin alkylates DNA, generates apurinic (AP) sites and reactive oxygen species (ROS), and causes DNA strand breaks. However, it is not clear whether these events occur inside cells. In the present study, we have determined the endogenous amount of AP sites and DNA strand breaks in genomic DNA and the amount of oxidative stress in a human pancreatic carcinoma cell line, MiaPaCa, treated with leinamycin by utilizing the aldehyde-reactive probe assay, the comet assay, and fluorescent probes, respectively. We demonstrated that AP sites are formed rapidly following exposure to leinamycin, and the number of AP sites was increased up to seven-fold in a dose-dependent manner. However, only 25-50% of these sites remain 2 h after media containing drug molecules were aspirated and replaced with fresh media. We also observed leinamycin-induced ROS generation and a concomitant increase in apoptosis of MiaPaCa cells. Because both AP sites and ROS have the potential to generate strand breaks in cellular DNA, the comet assay was utilized to detect damage to nuclear DNA in leinamycin-treated MiaPaCa cell cultures. Both alkaline and neutral electrophoretic analysis revealed that leinamycin produces both single- and double-stranded DNA damage in drug-treated cells in a dose-dependent manner. Taken together, the results suggest that rapid conversion of leinamycin-guanine (N7) adducts into AP sites to produce DNA strand breaks, in synergy with leinamycin-derived ROS, accounts for the exceedingly potent biological activity of this natural product.
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