Abstract
SUMMARYWe 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.
Highlights
Combination therapy, in which two or more anti-cancer agents are applied in combination, has more promise than monotherapy and is being assessed in multiple clinical trials
Drosophila screen identifies 16 natural products that enhance the effect of radiation We began by screening through Diversity Set I from the National Cancer Institute (NCI)-DTP, which consists of 1990 molecules chosen for chemical structural diversity and not for biological activity
We chose the Natural Product Set, from the National Cancer Institute Developmental Therapeutics Program (NCI-DTP), which contains 235 small molecules derived from natural sources
Summary
Combination therapy, in which two or more anti-cancer agents are applied in combination, has more promise than monotherapy and is being assessed in multiple clinical trials (www.clinicaltrials.gov). Most new combinations being assessed, were identified empirically and might not be the best combinations available. We developed a proprietary screen (US Patent No 7,695,899) to identify from the onset molecules that are effective in vivo in combination with radiation, a standard cancer therapy This screen takes advantage of similarities in radiation biology between mammalian tumors and organ primordia of Drosophila larvae. Both are capable of regeneration through ‘accelerated repopulation’, in which surviving cells after radiation treatment proliferate even faster than before (Jaklevic and Su, 2004; Hall and Giaccia, 2005; Jaklevic et al, 2006).
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