title: A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer.
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.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309-80347, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Gladstone
authors.forename: Barbara
authors.initials: B
authors.lastname: Frederick
authors.forename: Di
authors.initials: D
authors.lastname: Zheng
authors.forename: Anthony
authors.initials: A
authors.lastname: Edwards
authors.forename: Petros
authors.initials: P
authors.lastname: Yoon
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stickel
authors.forename: Tessie
authors.initials: T
authors.lastname: DeLaney
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chan
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Tin Tin
authors.initials: TT
authors.lastname: Su
mesh_terms: D000818:Animals; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis / Q000187:drug effects; D011839:Radiation, Ionizing; D023041:Xenograft Model Antitumor Assays
chemical_list: D001688:Biological Products; D010456:Peptides, Cyclic; C018234:bouvardin; D017239:Paclitaxel