Synthetic lethal activity of benzophenanthridine alkaloids from Zanthoxylum coco against BRCA1-deficient cancer cells

IRIS A. GARCIA; MARÍA F. PANSA; ADRIANA D. PACCIARONI; MANUELA GARCÍA; MARIA L. GONZALEZ; .JUAN C. OBERTI,; JOSÉ L. BOCCO; MARIA C. CARPINELLI; GLORIA E. BARBOZA; VIVIANA E. NICOTRA; GASTON SORIA

Frontiers in Phaemacology

Frontiers

Año: 2020 vol. 11

everal 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 Lab, 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 Zhanthoxylum 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-def