Synthetic lethal activity of benzophenanthridine alkaloids from Zanthoxylum coco against BRCA1-deficient cancer cells

GARCIA I.A.; PANSA M.F.; PACCIARONI A.D.; GARCÍA M.; GONZÁLEZ M.L.; OBERTI J.C.; BOCCO J.L.; CARPINELLA M. C.; BARBOZA G.; NICOTRA V.; SORIA G.

Frontiers in Pharmacology

Frontiers Media S.A.

Año: 2020 vol. 11

1663-9812

Several plants from South America show strong antitumoral properties based on anti-proliferative and/or pro-apoptotic activities. In this work we aimed to identify selective cytotoxic compounds that target BRCA1-deficient cancer cells by Synthetic Lethality (SL) induction. Using a high-throughput screening technology developed in our Lab, we analyzed a collection of extracts from 46 native plant species from Argentina using a wide dose-response scheme. A highly selective SL-induction capacity was found in an alkaloidal extract from Zhanthoxylum coco (Fam. Rutaceae). Bio-guided fractionation coupled to HPLC led to the identification of active benzophenanthridine alkaloids. The most potent SL activity was found with the compound oxynitidine, which showed a remarkably low relative abundance in the active fractions. Further validation experiments were performed using the commercially available and closely related analog nitidine, which showed SL-induction activity against various BRCA1-deficient cell lines with different genetic backgrounds, even in the nanomolar range. Exploration of the underlying mechanism of action using BRCA1-KO cells revealed AKT and topoisomerases as the potential targets responsible of nitidine-triggered SL-induction. Taken together, our findings expose an unforeseen therapeutic activity of alkaloids from Zhanthoxylum-spp. that position them as novel lead molecules for drug discovery.