Evidence map›Paper›PMID 26056295›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2015

Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.

Sheng-Xiong Huang, Bong-Sik Yun, Ming Ma, Hirak S Basu, Dawn R Church, Gudrun Ingenhorst, Yong Huang, Dong Yang, Jeremy R Lohman, Gong-Li Tang and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed
5.9field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed, 49 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Article
  6. Review
  7. Review
  8. Review
  9. Biosynthesis of Largimycins inACS chemical biology · 2022
    Article
  10. Review
  11. Review
  12. Article
  13. Review
  14. Review
  15. Review
  16. Review
  17. Article
  18. Article
  19. 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 · 2017
    Article
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 1 country.

Sheng-Xiong HuangDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
Bong-Sik YunDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
Ming MaDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
Hirak S BasuUniversity of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705;
Dawn R ChurchUniversity of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705;
Gudrun IngenhorstDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
Yong HuangDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
Dong YangDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
Jeremy R LohmanDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
Gong-Li TangDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
Jianhua JuDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
Tao LiuDivision of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705;
George WildingUniversity of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705;
Ben ShenDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458; Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL 33458 shenb@scripps.edu.
University of Wisconsin–Madison · USScripps Research Institute · USUniversity of Wisconsin Carbone Cancer Center · US

Funding

AT-less Type I Polyketide SynthasesR01CA106150 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI SHEN, BEN · 2004 to 2015
$3.3M
NCI NIH HHS CA106150NCI NIH HHS R01 CA106150
6 · The paper itself

Abstract

Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for the 18-membered lactam backbone and the alkyl branch at C3 of LNM. We now report the isolation and characterization of leinamycin E1 (LNM E1) from S. atroolivacues SB3033, a ΔlnmE mutant strain of S. atroolivaceus S-140. Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells, these findings support the idea of exploiting ROS as a means to target cancer cells and highlight LNM E1 as a novel lead for the development of anticancer prodrugs activated by ROS. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis, setting the stage to investigate sulfur incorporation, as well as the tailoring steps that convert the nascent hybrid peptide-polyketide biosynthetic intermediate into LNM.

Indexed as

Antineoplastic AgentsCell Line, TumorCell ProliferationDose-Response Relationship, DrugHumansLactamsMacrolidesMagnetic Resonance SpectroscopyMaleMolecular StructureProdrugsProstatic NeoplasmsReactive Oxygen SpeciesStreptomycesThiazolesThionesAntineoplastic AgentsLactamsleinamycinMacrolidesProdrugsReactive Oxygen SpeciesThiazolesThionescancer targetingdrug discoverynatural productpathway engineeringsulfur metabolism

Identifiers

PMID26056295
PMCPMC4500275
OpenAlexW1751756418

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.