Alkaloid and acetogenin-rich fraction from Annona crassiflora fruit peel inhibits proliferation and migration of human liver cancer HepG2 cells.

Allisson B Justino,Andressa França,André L Saraiva,Maria F Leite,Foued Salmen Espindola,Rodrigo R Franco,Antonio C M L Filho,Rodrigo M Florentino,Matheus C Fonseca,Walid Elfalleh

doi:10.1371/journal.pone.0250394

Abstract

Plant species from Annonaceae are commonly used in traditional medicine to treat various cancer types. This study aimed to investigate the antiproliferative potential of an alkaloid and acetogenin-rich fraction from the fruit peel of Annona crassiflora in HepG2 cells. A liquid-liquid fractionation was carried out on the ethanol extract of A. crassiflora fruit peel in order to obtain an alkaloid and acetogenin-rich fraction (AF-Ac). Cytotoxicity, proliferation and migration were evaluated in the HepG2 cells, as well as the proliferating cell nuclear antigen (PCNA), vinculin and epidermal growth factor receptor (EGFR) expression. In addition, intracellular Ca2+ was determined using Fluo4-AM and fluorescence microscopy. First, 9 aporphine alkaloids and 4 acetogenins that had not yet been identified in the fruit peel of A. crassiflora were found in AF-Ac. The treatment with 50 μg/mL AF-Ac reduced HepG2 cell viability, proliferation and migration (p < 0.001), which is in accordance with the reduced expression of PCNA and EGFR levels (p < 0.05). Furthermore, AF-Ac increased intracellular Ca2+ in the HepG2 cells, mobilizing intracellular calcium stores, which might be involved in the anti-migration and anti-proliferation capacities of AF-Ac. Our results support the growth-inhibitory potential of AF-Ac on HepG2 cells and suggest that this effect is triggered, at least in part, by PCNA and EGFR modulation and mobilization of intracellular Ca2+. This study showed biological activities not yet described for A. crassiflora fruit peel, which provide new possibilities for further in vivo studies to assess the antitumoral potential of A. crassiflora, especially its fruit peel.

Highlights

Cancer represents one of the main challenges for medicine being one of the most critical problems of public health in the world
Isoboldine, isocorydine, anonaine, nuciferine, xylopine, stephalagine, liriodenine and atherospermidine were the alkaloids found in acetogenin-rich fraction from Annona crassiflora fruit peel (AF-Ac) [13, 28,29,30,31,32,33], whereas bullatanocin, bullatacin/squamocin, annomontacin and desacetyluvaricin/ isodesacetyluvaricin were the acetogenins found in AF-Ac [34] (Fig 1 and Table 1)
Acetogenins influences epidermal growth factor receptor (EGFR) signaling to induce cell cycle arrest and inhibit cytotoxic cell survival [58]. These findings indicate that EGFR and proliferating cell nuclear antigen (PCNA) signaling pathways might play a role in mediating the antiproliferative activity of AF-Ac on HepG2 cells

Summary

Introduction

Cancer represents one of the main challenges for medicine being one of the most critical problems of public health in the world. Hepatocellular carcinoma (HCC) is the seventh most. Antiproliferative potential of A. crassiflora fruit peel in human liver cancer cells. Council for Scientific and Technological Development (CNPq, https://www.gov.br/cnpq/ptbr).

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