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

Abstract

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.

Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells

“…In this work, we used a novel screening platform developed and validated by our group ( Carbajosa et al, 2019 ; García et al, 2020 ) to identify ROCK as novel targets for SL induction in BRCA2-deficient cells. Using commercially available, and clinically relevant, ROCKi (i.e.…”

Inhibitors of ROCK kinases induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells

“…In this work we used a novel screening platform developed and validated by our group (Carbajosa et al, 2019; Garcia et al, 2020) to identify ROCK as novel targets for SL induction in BRCA2 cells. Using commercially available, and clinically relevant, ROCKi (i.e.…”