The novel resveratrol derivative 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro

Abstract

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a well-known polyphenol that is present in grapes, peanuts, pine seeds, and several other plants. Resveratrol exerts deleterious effects on various types of human cancer cells. Here, we analyzed the cell death-inducing mechanisms of resveratrol-006 (Res-006), a novel resveratrol derivative in human liver cancer cells in vitro. Res-006 suppressed the viability of HepG2 human hepatoma cells more effectively than resveratrol (the IC 50 values were 67.2 and 354.8 μmol/L, respectively). Co-treatment with the ER stress regulator 4-phenylbutyrate (0.5 mmol/L) or the ROS inhibitor N-acetyl-L-cysteine (NAC, 1 mmol/L) significantly attenuated Res-006-induced HepG2 cell death, suggesting that pro-apoptotic ER stress and/or ROS may govern the Res-006-induced HepG2 cell death. We further revealed that treatment of HepG2 cells with Res-006 (65 μmol/L) immediately elicited the dysregulation of mitochondrial dynamics and the accumulation of mitochondrial ROS. It also collapsed the mitochondrial membrane potential and further induced ER stress and cell death. These events, except for the change in mitochondrial morphology, were prevented by the exposure of the HepG2 cells to the mitochondrial ROS scavenger, Mito-TEMPO (300-1000 μmol/L). The results suggest that Res-006 may kill HepG2 cells through cell death pathways, including the ER stress initiated by mitochondrial ROS accumulation. The cell death induced by this novel resveratrol derivative involves crosstalk between the mitochondria and ER stress mechanisms.

Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds

“…These experiments provide evidence of ER-mediated pro-apoptotic activity of pterostilbene in human esophageal cancer cells [ 80 ]. Res-006, a novel resveratrol derivative, induced cell death in human hepatoblastoma HepG2 cells by triggering ER stress and mitochondrial dysfunction, providing a rationale for the development of new resveratrol-derived molecules for cancer treatment targeting both mitochondria and ER stress [ 81 ]. The ER stress-mediated anticancer activity exerted by resveratrol and its analogos is summarized in Table 2 .…”

3,5-Diethoxy-3′-Hydroxyresveratrol (DEHR) Ameliorates Liver Fibrosis via Caveolin-1 Activation in Hepatic Stellate Cells and in a Mouse Model of Bile Duct Ligation Injury

“…Results of studies that explored the inhibitory effects of resveratrol on the proliferation of HSCs have implicated resveratrol as a promising candidate for the treatment of liver fibrosis [ 14 , 15 , 16 , 17 ]. Other studies have sought to improve the bioactivity of resveratrol [ 18 , 19 , 20 ]. For instance, trimethylated resveratrol is up to 100-fold more cytotoxic than normal resveratrol in vitro [ 18 , 20 ].…”

“…Other studies have sought to improve the bioactivity of resveratrol [ 18 , 19 , 20 ]. For instance, trimethylated resveratrol is up to 100-fold more cytotoxic than normal resveratrol in vitro [ 18 , 20 ].…”

Natural products and phytochemical nanoformulations targeting mitochondria in oncotherapy: an updated review on resveratrol

“…In fact, resveratrol stimulates apoptotic cell death through improving the oxidative phosphorylation [145]. The studies approve that the high concentration of resveratrol or long-term exposure to resveratrol is related to a perturbation in the oxidative-antioxidative balance leading to apoptotic cell death [146][147][148][149][150].…”