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

PANSA MF; PACCIARONI A; GARCÍA M; OBERTI JC; CARBAJOSA S; CAMPÓNICO P; PAVIOLO N; BARBOZA G; GOTTIFREDI V; BOCCO JL; NICOTRA VE; SORIA G

Simposio; Reunión Conjunta de Sociedades de Biociencias; 2017

Induction of synthetic lethality (SL) is a precision strategy which takes advantage of tumor mutations to induce selective tumor death. A high incidence type of breast and ovarian cancers are characterized by BRCA1/2 germline mutations, which can thus be used as a genetic background to screen for SL inducers. Natural products provide a vast source of compounds for drug development due to their great chemical diversity. Thus, the aim of this work was to search for synthetic lethality inducers in a library of plant extracts and pure compounds from Argentina. We used a cell-based screening platform that compares BRCA1/2 deficient with proficient cells. In this platform the three cells populations are co-cultured and simultaneously exposed to the plant extracts and pure compounds. Cell survival is calculated considering the ratio of BRCA-proficient and BRCA-deficient populations at the end of the experiment.We found one family of pure compounds that triggers SL in BRCA2-defficient cells and one active alkaline extract with SL activity against BRCA1-defficient cells. To identify the active/s compound/s in this extract we perform bio-guided fractionation using VLC and Sephadex chromatography. We found 3 members of the furoquinoline family of alkaloids as the most active compounds.