The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase

Jennifer D. Tibodeau, Linda M. Benson, Crescent R. Isham, Whyte G. Owen, Keith C. Bible

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of underlying molecular mechanisms, we now report that chaetocin is a competitive and selective substrate for the oxidative stress mitigation enzyme thioredoxin reductase-1 (TrxR1) with lower K m than the TrxR1 native substrate thioredoxin (Trx; chaetocin K m=4.6±0.6μM, Trx K m=104.7±26μM), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. Consistent with a role for TrxR1 targeting in the anticancer effects of chaetocin, overexpression of the TrxR1 downstream effector Trx in HeLa cells conferred resistance to chaetocin-induced, but not to doxorubicin-induced, cytotoxicity. As the TrxR/Trx pathway is of central importance in limiting cellular reactive oxygen species (ROS)-and as chaetocin exerts its selective anticancer effects via ROS imposition-the inhibition of TrxR1 by chaetocin has potential to explain its selective anticancer effects. These observations have important implications not just with regard to the mechanism of action and clinical development of chaetocin and related thiodioxopiperazines, but also with regard to the utility of molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents. Antioxid. Redox Signal. 11, 1097-1106.

Original languageEnglish (US)
Pages (from-to)1097-1106
Number of pages10
JournalAntioxidants and Redox Signaling
Volume11
Issue number5
DOIs
StatePublished - May 1 2009

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Thioredoxin-Disulfide Reductase
Thioredoxin Reductase 1
Antineoplastic Agents
Substrates
Reactive Oxygen Species
Thioredoxins
Oxidative stress
Oxidative Stress
chaetocin
Cytotoxicity
Biological Products
Remediation
HeLa Cells
Doxorubicin
Oxidation-Reduction
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry
  • Medicine(all)

Cite this

The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase. / Tibodeau, Jennifer D.; Benson, Linda M.; Isham, Crescent R.; Owen, Whyte G.; Bible, Keith C.

In: Antioxidants and Redox Signaling, Vol. 11, No. 5, 01.05.2009, p. 1097-1106.

Research output: Contribution to journalArticle

Tibodeau, Jennifer D. ; Benson, Linda M. ; Isham, Crescent R. ; Owen, Whyte G. ; Bible, Keith C. / The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase. In: Antioxidants and Redox Signaling. 2009 ; Vol. 11, No. 5. pp. 1097-1106.
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