Frontiers in Pharmacology (Dec 2020)

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

  • Iris A. García,
  • Iris A. García,
  • Maria Florencia Pansa,
  • Maria Florencia Pansa,
  • Adriana Del Valle Pacciaroni,
  • Adriana Del Valle Pacciaroni,
  • Manuela E. García,
  • Manuela E. García,
  • Maria Laura Gonzalez,
  • Juan Carlos Oberti,
  • Juan Carlos Oberti,
  • José Luís Bocco,
  • José Luís Bocco,
  • Maria Cecilia Carpinella,
  • Gloria E. Barboza,
  • Gloria E. Barboza,
  • Viviana E. Nicotra,
  • Viviana E. Nicotra,
  • Gastón Soria,
  • Gastón Soria

DOI
https://doi.org/10.3389/fphar.2020.593845
Journal volume & issue
Vol. 11

Abstract

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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.

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