A novel combined resveratrol/berberine phytochemotheraputic using the HePG2 cell line as a model for the treatment of hepatocarcinoma

Abstract

The results presented herein show that at clinically relevant concentrations (0-30 µM), the well-tolerated phytochemical berberine (BER) induces cell death in cultured human hepatocarcinoma (HepG2) cells as a model for liver cancer, primarily via apoptosis. Similar, relatively low-concentration single treatments using the structurally related phytochemical resveratrol (RSV), had little or no effect on cell viability but inhibited the cell cycle, while simultaneously increasing the strength of cellular adhesion. When used in combination, an RSV/BER cotreatment appeared to retain the ability of a single RSV treatment to increase cellular adhesion, but also induced a massive loss in hepatocarcinoma cellular viability, inducing cell death in more than 90% of cells. This model, therefore, suggests that it may be possible to use RSV to stabilise hepatocarcinomas against metastasis while using cotreatment with BER to simultaneously induce cell death. By measuring the changes in the activity of the pleiotropic enzyme transglutaminase 2 (TGM2), which is known to be overexpressed in hepatocarcinoma and many other tumours, we hypothesise a role for this enzyme in the activities of these two phytochemicals, and propose the potential use of this RSV/ BER cotreatment as a chemotherapeutic in TGM2+ hepatocarcinomas.

Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer

“…In addition, BBR hydrochloride induced cell proliferation and apoptosis of A549 cells by increasing the activity of the Bcl-2/Bax signaling pathway and inhibiting the Janus kinase 2 (Jak2)/vascular endothelial growth factor (VEGF)/NF-κB/transcription factor AP-1 (AP-1) signaling pathway ( Li et al, 2018b ). Second, co-administration can significantly improve the bioavailability and anticancer effects of BBR, such as theophylline ( Hashemi-Niasari et al, 2018 ), cinnamaldehyde ( Meng et al, 2017 ), icotinib ( Chen et al, 2021 ), evodiamine ( Du et al, 2017 ), HMQ1611 ( Dai et al, 2019 ), s-allyl-cysteine ( Sengupta et al, 2017 ), resveratrol ( D’arcy et al, 2021 ), and Dox ( Zhang et al, 2020b ). All these factors may have a synergistic effect with BBR.…”

A review of biologically active flavonoids as inducers of autophagy and apoptosis in neoplastic cells and as cytoprotective agents in non‐neoplastic cells

“…Several phytochemicals (compounds derived from plants), including the sub‐group of phytochemicals that are collectively known as the flavonoids, have been identified as modulators of a variety of intracellular pathways involved in tumor progression and/or the induction of cell death. For example, the phytochemicals resveratrol and berberine have been observed to prevent metastasis of hepatocarcinoma cells and to initiate cell death by apoptosis (D'Arcy et al, 2021). A number of particularly interesting phytochemicals also seem to act as chemopreventatives by neutralizing carcinogenic compounds such as ROS before they have the opportunity to react with and damage vital components of the cell, such as DNA.…”

“….1 | The protective effects of quercetin Quercetin has been shown to slow down the accumulation of damage to cells during the aging process and has therefore been touted by many as an anti-aging compound. Together with phytochemicals such as resveratrol (D'Arcy, 2020) and berberine(D'Arcy et al, 2021) quercetin's ability to slow down the accumulation of damage to cells seems to result from its antioxidant role; however, its modulation of autophagic pathways also has a role in its anti-aging mechanisms.…”