The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation

C. R. Isham, J. D. Tibodeau, A. R. Bossou, J. R. Merchan, K. C. Bible

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Background: We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin reductase; we now detail its effects in solid tumours. Methods: Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells. Results: NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2-10 nM IC50s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho 0 cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation. Conclusion: Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.

Original languageEnglish (US)
Pages (from-to)314-323
Number of pages10
JournalBritish journal of cancer
Volume106
Issue number2
DOIs
StatePublished - Jan 17 2012

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Keywords

  • angiogenesis
  • apoptosis
  • hypoxia
  • reactive oxygen species
  • thioredoxin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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