Natural Products as a source of novel synthetic lethality inducers in BRCA-deficient cancer cells.

MARÍA FLORENCIA PANSA; ADRIANA PACCIARONI; MANUELA GARCIA; JUAN CARLOS OBERTI; SOFÍA CARBAJOSA; PAOLA CAMPODÓNICO; NATALIA PAVIOLO; GLORIA BARBOZA; VANESA GOTTIFREDI; JOSÉ LUIS BOCCO; VIVIANA NICOTRA; GASTÓN SORIA

Buenos Aires

Congreso; Reunión conjunta de sociedades de biociencias; 2017

Induction of synthetic lethality (SL) is a precision strategy whichtakes advantage of tumor mutations to induce selective tumor death.A high incidence type of breast and ovarian cancers are characterizedby BRCA1/2 germline mutations, which can thus be used as agenetic background to screen for SL inducers.Natural products provide a vast source of compounds for drug developmentdue to their great chemical diversity. Thus, the aim of thiswork was to search for synthetic lethality inducers in a library of plantextracts and pure compounds from Argentina. We used a cell-basedscreening platform that compares BRCA1/2 deficient with proficientcells. In this platform the three cells populations are co-cultured andsimultaneously exposed to the plant extracts and pure compounds.Cell survival is calculated considering the ratio of BRCA-proficientand BRCA-deficient populations at the end of the experiment.We found one family of pure compounds that triggers SL inBRCA2-defficient cells and one active alkaline extract with SL activityagainst BRCA1-defficient cells. To identify the active/s compound/s in this extract we perform bio-guided fractionation usingVLC and Sephadex chromatography. We found 3 members of thefuroquinoline family of alkaloids as the most active compounds.Keywords: Synthetic lethality, natural products, breast cancer,BRCA1/2, cell-based screening