The red wine component ellagic acid induces autophagy and exhibits anti‐lung cancer activity in vitro and in vivo

Abstract

Red wine consists of a large amount of compounds such as resveratrol, which exhibits chemopreventive and therapeutic effects against several types of cancers by targeting cancer driver molecules. In this study, we tested the anti‐lung cancer activity of 11 red wine components and reported that a natural polyphenol compound ellagic acid (EA) inhibited lung cancer cell proliferation at an efficacy approximately equal to that of resveratrol. EA markedly increased the expression of the autophagosomal marker LC3‐II as well as inactivation of the mechanistic target of rapamycin signalling pathway. EA elevated autophagy‐associated cell death by down‐regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA‐induced autophagy of lung cancer cells. Treating tumour‐bearing mice with EA resulted in significant inhibition of tumour growth with suppression of CIP2A levels and increased autophagy. In addition, EA potentiated the inhibitory effects of the natural compound celastrol on lung cancer cells in vitro and in vivo by enhancing autophagy and down‐regulating CIP2A. These findings indicate that EA may be a promising chemotherapeutic agent for lung cancer, and that the combination of EA and celastrol may have applicability for the treatment of this disease.

Ellagic acid induces esophageal squamous cell carcinoma cell apoptosis by modulating SHP‐1/STAT3 signaling

“…14 The anticarcinogenic effect of EA has been shown in some types of tumors, including prostate cancer, lung cancer, osteosarcoma, breast cancer, and so forth. [15][16][17][18] Consistent with previous studies, EA also showed good antitumor activity in ESCC. We found that EA inhibited ESCC cell survival by inducing cell apoptosis.…”

Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway

“…Ellagic acid has shown multiple protective effects during brotic diseases such as liver brosis, pancreatic brosis and cardiac brosis [23][24][25]. Ellagic acid promoted apoptosis and autophagy, suppressed Wnt/β-catenin and mTOR pathways in tumor cells [26][27][28]. In addition, previous studies have reported that Ellagic acid could attenuate BLM-induced pulmonary brosis in rats [29,30], but the therapeutic effect of BLM-induced pulmonary brosis in mice and its mechanism are not clear.…”

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies

“…Hydroxybenzoic acid derivatives have been studied for their role in modulating autophagy and cancer cell growth. Duan et al reported that ellagic acid (10-50 µM) activated autophagy, but not apoptosis, in lung cancer cells (HOP62 and H1975), and in tumor-bearing mice (40 mg/kg, i.p., every 2 days, for 22 days), as demonstrated by the formation of LC3-positive autophagosomes, the increase in LC3 II, ATG5 and the reduced levels of p62 [238]. Similarly, ellagic acid (36.6 µM) inhibited cell growth and the invasiveness of ovarian cancer SKOV-3 cells and stimulated apoptosis by activating cytotoxic autophagy, as indicated by the increase in the levels of Beclin 1, ATG5, LC3I/II and decrease in p62 [239].…”

“…Similarly, ellagic acid (36.6 µM) inhibited cell growth and the invasiveness of ovarian cancer SKOV-3 cells and stimulated apoptosis by activating cytotoxic autophagy, as indicated by the increase in the levels of Beclin 1, ATG5, LC3I/II and decrease in p62 [239]. In addition, it was shown that ellagic acid activated autophagy through the downregulation of mTORC1 and Akt, and the activation of AMPK [238,239]. The activation of apoptotic and autophagic cell death was also reported for punicalagin, an ellagitannin isolated from the fruit of Punica granatum L. trees.…”