Synthetic Lethal Activity of Benzophenanthridine Alkaloids From Zanthoxylum coco Against BRCA1-Deficient Cancer Cells

GARCÍA, IRIS A.; PANSA, MARIA FLORENCIA; GONZALEZ, MARIA LAURA; GARCÍA, MANUELA E.; CARPINELLA, MARIA CECILIA; BOCCO, JOSÉ LUÍS; SORIA, GASTÓN; NICOTRA, VIVIANA E.; PACCIARONI, ADRIANA DEL VALLE; OBERTI, JUAN CARLOS; BARBOZA, GLORIA E.

Frontiers in Pharmacology

Frontiers Media S.A.

Año: 2020 vol. 11

Several plants from South America show strong antitumoral properties based on antiproliferative 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 laboratory, 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 Zanthoxylum 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 nitidinetriggered SL-induction. Taken together, our findings expose an unforeseen therapeutic activity of alkaloids from Zanthoxylum-spp. that position them as novel lead molecules for drug discovery.