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.
Highlights
BRCA1 is highly characterized as a tumor suppressor gene that was originally identified in hereditary breast and ovarian cancers (King et al, 2012; Takaoka and Miki, 2018)
To identify novel Synthetic Lethality (SL) interactions in BRCA1 deficient contexts, we used an adaptation of a phenotypic screening platform developed in our Lab (Carbajosa et al, 2019; Villafañez et al, 2019) to evaluate a collection of plant extracts
Hits were defined by a variation greater than 3 SD on two values derived from the differential impact of the extracts on the BRCA1-deficient vs. BRCA1-proficient populations: 1) SL induction fold: derived from the ratio of the proportion of BRCA1-proficient/BRCA1-deficient cells in each well and 2) survival difference: derived from the subtraction of the survival of the BRCA1-deficient from the BRCA1-proficient population
Summary
BRCA1 is highly characterized as a tumor suppressor gene that was originally identified in hereditary breast and ovarian cancers (King et al, 2012; Takaoka and Miki, 2018). A strategy that takes advantage of the genetic differences of cancer cells to achieve their selective death is known as synthetic lethality (SL), which consists in the simultaneous inactivation of compensatory or redundant molecular pathways (Canaani, 2013; Nijman and Friend, 2013; Ryan et al, 2018). In this sense, in a BRCA1-deficient context, the inhibition of specific molecular targets that compensate BRCA1 functions could trigger SL. Given that many types of resistance mechanisms to PARPi are already being described (D’Andrea, 2018; Noordermeer and van Attikum, 2019), there is a major interest in developing alternative SL strategies to target BRCA1 deficiency from different angles
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