ALKALOIDS WITH SYNTHETIC LETHAL ACTIVITY AGAINST BRCA-DEFICIENT CELLS ISOLATED FROM Zanthoxylum coco

PANSA, M.F.; PACCIARONI, A.; ANGIOLINI, V.; CARBAJOSA, S.; BARBOZA, G.E.; BOCCO, J.L.; NICOTRA, V.; SORIA, G.R.

Paraná

Congreso; 54th Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The design of drug discovery strategies for cancer research is one of the most challenging efforts to develop novel targeted therapies. Syntheticlethality (SL) is a state-of-the-art precision strategy for cancer treatment that is based on the induction of selective toxicity against cancerous cellswith certain genetic defects. Since mutations or epigenetic down-regulation of BRCA genes are known drivers of hereditary types of breast andovarian cancers, they can be used as tools in phenotypic screenings to identify novel synthetic lethality inducers.Due to their broad chemicaldiversity, natural products are an important source of lead molecules for drug discovery. In this work we evaluated pure compounds and extractsfrom ≈200 plant species from Argentina using an innovative screening platform based on automated flow cytometry. We found that the alkalineextract from Zanthoxilum coco induce SL in BRCA-deficient cells. To identify the active metabolite/s, we performed bio-guided isolationfollowing a sub-fractionation process and semi-preparative HPLC. Using spectroscopic methods (NMR) we were able to identify a set ofbenzophenantridine alkaloids as the responsible compounds of this activity. Early validation experiments using BRCA-KO cell lines andcommercially available alkaloids from the same family confirmed our findings. In conclusion, this work put forward the benzophenantridinealkaloids from Zanthoxylum coco as promising molecules for target identification and drug development to treat BRCA-deficient cancers.