Comparison of the Impact of Xanthohumol and Phenethyl Isothiocyanate and Their Combination on Nrf2 and NF-κB Pathways in HepG2 Cells In Vitro and Tumor Burden In Vivo

Abstract

Background: Increasing evidence suggests that combinations of phytochemicals are more efficient than single components in the modulation of signaling pathways involved in cancer development. In this study, the impact of phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol, (X), and resveratrol (RES) and their combinations on the activation and expression of Nrf2 and NF-κB in human hepatocytes and HCC cells were evaluated. Methods: THLE-2 and HepG2 cells were exposed to single phytochemicals and their combinations for 24 h. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cells survival were assessed. The tumor burden was evaluated in mice carrying xenografts. Results: All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells. The increased expression of NQO1 (~90%) was associated with increased ROS generation. X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression. In contrast to single phytochemicals, X + PEITC induced apoptosis. Moderate reduction of tumor burden in mice carrying xenografts following X and PEITC or their combination was observed. Conclusions: Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.

Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial

“…Thus, future mechanistic studies shall focus on p53 reactivation and redox-modulation pathways. Furthermore, there could be other mechanisms behind the cancer-stabilizing mechanism of PEITC, such as epigenetic modulation [62], suppression of inflammatory signaling NF-κB [59,63,64], and inhibition of epithelial-mesenchymal transition as invasion machinery [65]. Future metabolomic studies of clinical specimens from patients receiving Nutri-PEITC Jelly would be worthwhile to characterize the molecular pathways [66].…”

Is Bitterness Only a Taste? The Expanding Area of Health Benefits of Brassica Vegetables and Potential for Bitter Taste Receptors to Support Health Benefits

“…The major impact of the interaction of ITCs with the Nrf2/NF-κB pathway(s) is the control of oxidative stress and chronic inflammation [ 48 ]. Many studies have reported that purified ITCs (including SF, allyl isothiocyanate (AITC), BITC, PEITC) or brassica diets increase Nrf2-dependent antioxidant gene expression (NQO1, superoxide dismutase (SOD), heme oxygenase-1(HO-1), and others) and/or reduce proinflammatory mediators’ gene expression (NF-κB, IL-6, cyclooxygenase 2 (COX2), vascular cell adhesion molecule 1 (VCAM-1)) in cell and animal models of cancer or inflammation [ 30 , 56 , 57 , 58 ]. ITC-induced bioactivities reported using cell culture and animal studies typically show consistent results, since these models’ potential variables, including food and growing conditions, are precisely controlled.…”

Sodium Butyrate Enhances Curcuminoids Permeability through the Blood-Brain Barrier, Restores Wnt/β-Catenin Pathway Antagonists Gene Expression and Reduces the Viability of Glioblastoma Cells

“…Numerous epidemiological studies demonstrated the relationship between diet and cancer and the potential of dietary components, particularly polyphenols as promising anticancer and chemopreventive agents [3,4]. Curcumin, also known as diferuloylmethane 2 of 21 (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-hepadiene-3,5-dione), is a natural polyphenol extracted from the rhizome of Curcuma longa.…”