NATURAL PRODUCTS AS A SOURCE OF NOVEL SYNTHETIC LETHALITY INDUCERS IN BRCA-DEFICIENT CANCER CELLS

JOSÉ L BOCCO; NATALIA SOLEDAD PAVIOLO; JUAN CARLOS M OBERTI ; MARIA F. PANSA; RAMIRO GASTÓN SORIA; VANESA GOTTIFREDI; PAOLA CAMPODÓNICO; MANUELA E GARCÍA ; VIVIANA E NICOTRA; GLORIA E BARBOZA; SOFIA CARBAJOSA; ADRIANA PACCIARONI

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/sin 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.