Artículo
Synthetic lethal activity of benzophenanthridine alkaloids from Zanthoxylum coco against BRCA1-deficientcancer cells
García, Iris Alejandra
; Pansa, Maria Florencia
; Pacciaroni, Adriana del Valle; García, Manuela Emila
; Gonzalez, Maria Laura; Oberti, Juan Carlos María
; Bocco, Jose Luis
; Carpinella, Maria Cecilia
; Barboza, Gloria Estela
; Nicotra, Viviana Estela
; Soria, Gastón
Fecha de publicación:
12/2020
Editorial:
Frontiers Media S.A.
Revista:
Frontiers in Pharmacology
e-ISSN:
1663-9812
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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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Articulos(IMBIV)
Articulos de INST.MULTIDISCIPL.DE BIOLOGIA VEGETAL (P)
Articulos de INST.MULTIDISCIPL.DE BIOLOGIA VEGETAL (P)
Citación
García, Iris Alejandra; Pansa, Maria Florencia; Pacciaroni, Adriana del Valle; García, Manuela Emila; Gonzalez, Maria Laura; et al.; Synthetic lethal activity of benzophenanthridine alkaloids from Zanthoxylum coco against BRCA1-deficientcancer cells; Frontiers Media S.A.; Frontiers in Pharmacology; 11; 12-2020; 1-10
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