An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery

Abstract

SUMMARYAnti-cancer drug development involves enormous expenditure and risk. For rapid and economical identification of novel, bioavailable anti-tumour chemicals, the use of appropriate in vivo tumour models suitable for large-scale screening is key. Using a Drosophila Ras-driven tumour model, we demonstrate that tumour overgrowth can be curtailed by feeding larvae with chemicals that have the in vivo pharmacokinetics essential for drug development and known efficacy against human tumour cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumour model. In a proof-of-principle pilot screen of 2000 compounds, we identify the glutamine analogue, acivicin, a chemical with known activity against human tumour cells, as a potent and specific inhibitor of Drosophila tumour formation. RNAi-mediated knockdown of candidate acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible crucial target of acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumours are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economical tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering widespread applications in drug development.

Hippo signaling promotes JNK-dependent cell migration

“…Drosophila has been widely considered as an excellent organism to address cancer-related problems for the past decade (45,46), several in vivo cell invasion and metastasis models were established to dissect genetic details of cancer progression (22,(47)(48)(49). Here, using Drosophila wing epithelium as a major model, we bring forward an interesting model that elevated ; (E and G) dpp-Gal4 UAS-ban-sponge/UAS-Rox8.RNAi, puc E69 ; (H) ptc-Gal4 UAS-GFP/UAS-Hpo; tub-Gal80ts/UAS-Rox8.RNAi; and (I) ptc-Gal4 UAS-GFP/+; UAS-yki.RNAi, UAS-Dcr2/UAS-Rox8.RNAi.…”

In vivo Antibacterial Activity of Green Algae Ulva reticulata against Staphylococcus aureus in Drosophila Model of Infection

“…[20][21][22] To the latest, D. melanogaster has been recognized as a promising disease model to discover new drug candidates and/or their respected targets. [23][24][25] Drosophila melanogaster have been widely suggested as a suitable host for several pathogenic bacteria known to cause devastating infections in humans such as Staphylococcus aureus, 11,26 Pseudomonas aeruginosa, 27 Listeria monocytogenes, 28 Burkholderia spp., 29 and Bacillus anthracis. 30 In addition to that, with its high degree of genetic similarity with human, cheap maintaining costs, and poses almost no ethical issues, 10,16,17 D. melanogaster offers great advantages as an in vivo model system in antibacterial drug discovery research.…”

Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back

“…After a specific period of time, the effect of the drug on the cancer phenotype can be quantified by various means (Figure 4). The most commonly used end points are: (i) viability of the organism; (ii) eclosion of the pupa/adult; (iii) luciferase activity; (iv) GFP expression; and (v) other biochemical assays [19][20][21][22]. Whole-organism-based drug screening permits assessment of drug absorption, distribution, metabolic stability, and toxicity and reduces the possibilities of false positives.…”