Abstract
Seaweeds are one of the largest producers of biomass in the marine environment and a source of multiple bioactive metabolites with valuable health benefits. Among these, phlorotannins have been widely recognized for their promising bioactive properties. The potential antitumor capacity of Fucus vesiculosus-derived phlorotannins remains, however, poorly explored, especially in gastrointestinal tract-related tumors. Therefore, this work aimed to evaluate the cytotoxic properties and possible mechanisms by which F. vesiculosus crude extract (CRD), phlorotannin-rich extract (EtOAc), and further phlorotannin-purified fractions (F1–F9) trigger cell death on different tumor cell lines of the gastrointestinal tract, using flow cytometry. The results indicate that F. vesiculosus samples exert specific cytotoxicity against tumor cell lines without affecting the viability of normal cells. Moreover, it was found that, among the nine different phlorotannin fractions tested, F5 was the most active against both Caco-2 colorectal and MKN-28 gastric cancer cells, inducing death via activation of both apoptosis and necrosis. The UHPLC-MS analysis of this fraction revealed, among others, the presence of a compound tentatively identified as eckstolonol and another as fucofurodiphlorethol, which could be mainly responsible for the promising cytotoxic effects observed in this sample. Overall, the results herein reported contribute to a better understanding of the mechanisms behind the antitumor properties of F. vesiculosus phlorotannin-rich extracts.
Highlights
Cancer is the second global leading cause of death and, according to the World HealthOrganization (WHO), in 2020, it was responsible for nearly 10 million deaths
Fucus vesiculosus phlorotannins were shown to hold potential as antitumor agents against both gastric and colon cancer because some of its fractions were capable of inducing selective cytotoxic effects towards tumor cell lines, but not on normal cell lines
The collected data suggest that F1 antitumor activity might result in part from induction of cell cycle arrest at the S phase, while F5 exerts its effect via a remarkable stimulation of apoptosis and necrosis
Summary
Cancer is the second global leading cause of death and, according to the World HealthOrganization (WHO), in 2020, it was responsible for nearly 10 million deaths. Infection by Helicobacter pylori is one of the most important risk factors for the development of stomach cancer, while inflammatory bowel disease, including Chron’s disease and ulcerative colitis, is a major factor in the development of colorectal cancer [2,3] In this field, phlorotannins, i.e., phloroglucinol-based phenolic compounds exclusively from brown algae, have drawn much attention during recent years thanks to their promising bioactive properties, their antitumor potential evidenced against different types of cancer [4]. Induction of apoptosis is one of the most common mechanisms activated by these compounds, being described for phlorotannins extracted from multiple seaweed species and in numerous tumor cell lines including HepG2 and Hep3B human hepatoma, MCF-7 human breast cancer, S180 murine sarcoma, SKOV3 human ovarian cancer, and PancTu1 human pancreatic cancer, among several others [5,6,7,8,9,10]. Compounds such as phloroglucinol, eckol, dieckol, and eckstolonol have been repeatedly reported for their abilities to stimulate the expression of distinct pro-apoptotic proteins, including several caspases (-3, -7, -8, and -9), cytochrome c, Bid and Bim, Bak and Bax, and p53 [5,6,9,11,12,13,14], while inhibiting the expression of anti-apoptotic proteins such as
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