A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer

Mara Gladstone, Barbara Frederick, Di Zheng, Anthony Edwards, Petros Yoon, Stefanie Stickel, Tessie DeLaney, Daniel C. Chan, David Raben, Tin Tin Su

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

We described previously a screening protocol in Drosophila melanogaster that allows us to identify small molecules that increase the killing effect of ionizing radiation in vivo in a multicellular context. The ability of this screen to identify agents that enhance the effect of radiation in human cancer models has been validated in published proof-of-concept studies. Here we describe an agent, identified by screening through two National Cancer Institute (NCI) small molecule libraries in Drosophila, that increases the effect of radiation. This agent, Bouvardin (NSC 259968), inhibits the elongation step of protein synthesis. We find that Bouvardin enhances the killing effect of X-rays in both Drosophila larvae and in human cancer cells. More detailed analysis showed that Bouvardin also increases the effect of radiation in clonogenic assays and in human cancer xenografts in mice. Finally, we present data that Bouvardin can also increase the efficacy of taxol. Regulation of translation is important to cancer biology. Current therapies target every aspect of cancer cell proliferation from growth factor signaling to cell division, with the exception of translation elongation. Our identification of Bouvardin as an enhancer of radio- and chemo-therapeutic agents suggests that targeting this niche has the potential to improve existing cancer therapies.

Original languageEnglish (US)
Pages (from-to)342-350
Number of pages9
JournalDMM Disease Models and Mechanisms
Volume5
Issue number3
DOIs
StatePublished - May 1 2012

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bouvardin
Ionizing radiation
Paclitaxel
Ionizing Radiation
Drosophila
Radiation Effects
Neoplasms
Radiation
Elongation
Screening
Cells
Molecules
Small Molecule Libraries
Cell proliferation
Heterografts
National Cancer Institute (U.S.)
Therapeutics
Assays
Drosophila melanogaster
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer. / Gladstone, Mara; Frederick, Barbara; Zheng, Di; Edwards, Anthony; Yoon, Petros; Stickel, Stefanie; DeLaney, Tessie; Chan, Daniel C.; Raben, David; Su, Tin Tin.

In: DMM Disease Models and Mechanisms, Vol. 5, No. 3, 01.05.2012, p. 342-350.

Research output: Contribution to journalArticle

Gladstone, Mara ; Frederick, Barbara ; Zheng, Di ; Edwards, Anthony ; Yoon, Petros ; Stickel, Stefanie ; DeLaney, Tessie ; Chan, Daniel C. ; Raben, David ; Su, Tin Tin. / A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer. In: DMM Disease Models and Mechanisms. 2012 ; Vol. 5, No. 3. pp. 342-350.
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