High-throughput screening of synthetic lethality inducers in cancer cells using complete extracts and isolated compounds from plants and fungi from Argentina

PANSA F.; CARBAJOSA S.; GARCIA A.; TORRES N. ; PAVIOLO N.; CAMPODÓNICO P.; VILLAFAÑEZ F; NICOTRA V.; BARBOZA G.; PALACIOS S.; RUIZ G. M.; ASIS R.; THEUMER M.; BOCCO J.L.; GOTTIFREDI V. ; CARPINELLA C.; SORIA G.

Termas de Chillán

Simposio; IX International Symposium on natural products chemistry and applicaions; 2016

One of the current challenges in the fight against cancer is the identification of compounds with selective tumor cytotoxicity. A precision strategy of this kind that lead to promising results in recent years is the induction of synthetic lethality, which takes advantage of tumor mutations to induce selective tumor lethality. The homologous recombination (HR) pathway is a strategic target for synthetic lethality because of its important role in double strand break repair, and because HR loss is a key feature of certain types of breast and ovarian cancer (i.e. BRCA1 and BRCA2 deficient cancers). The aim of this work is to screen natural products to identify targets that can induce new synthetic lethality inducers in HR-deficient cells. To achieve this a high-throughput screening platform based on flow cytometry was developed. This platform relies on the generation of HR-proficient and HR-deficient cell lines of isogenic origin that emulate BRCA1 and BRCA2 deficient cancers, and that can be simultaneously exposed to the tested extracts and pure compounds. We use fluorescent markers to identify each population, assessing cell survival by the ratio of HR-proficient and HR-deficient populations at the end of the experiment. In this poster we show the development of the platform, the fine-tuning setup using drugs known inducers of synthetic lethality and the results of a pilot screening with 183 complete extracts from plants and fungi from Argentina.