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

• Main Authors: Iris A. García, Maria Florencia Pansa, Adriana Del Valle Pacciaroni, Manuela E. García, Maria Laura Gonzalez, Juan Carlos Oberti, José Luís Bocco, Maria Cecilia Carpinella, Gloria E. Barboza, Viviana E. Nicotra, Gastón Soria
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-12-01
• Series: Frontiers in Pharmacology
• Subjects: natural products; Zanthoxylum coco; oxynitidine; nitidine; drug discovery; BRCA1
• Online Access: https://www.frontiersin.org/articles/10.3389/fphar.2020.593845/full

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 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 nitidine-triggered 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.