Acteoside‐mediates chemoprevention of experimental liver carcinogenesis through STAT‐3 regulated oxidative stress and apoptosis

Abstract

In the absence of an effective therapy against Hepatocellular Carcinoma (HCC), chemoprevention remains an important strategy to circumvent morbidity and mortality. Here, we examined chemopreventive potential of Acteoside (ACT), a plant derived phenylethanoid glycoside against an environmental and dietary carcinogen, diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. ACT treatment (0.1 and 0.3% supplemented with diet) started 2 weeks before DEN challenge and continued for 18 weeks thereafter, showed a remarkable chemopreventive activity. ACT treatment resulted in reduced HCC nodules. Histopathology showed progressive tissue damage, necrosis (5 weeks), hepatocytic injury (10 weeks), anisonucleosis with presence of prominent nucleoli, sinusidal dilations, and lymphomono nuclear inflammation (18 weeks). Biochemical analysis showed hepatocytic injury (raised ALT, p < 0.001), inflammation [IL-6, IFN-γ (p < 0.05), and TNF-α (p < 0.001)], apoptosis [elevated Caspase-3 (p < 0.001)]. ACT at 0.1 and 0.3% ameliorated DEN-induced pre-hepatocarcinogenic manifestations. Mechanistic studies of ACT chemoprevention was elucidated using Hep3B cells with an aim to develop an in vitro DEN-induced toxicity model. Hep3B was found to be a reliable and more sensitive towards DEN toxicity compared to HepG2 and HuH7 cells. ACT prevented DEN-induced cytotoxicity (p < 0.001), DNA damage, and genotoxicity (micronuclei test, DNA ladder test, Hoechst staining, cell cycle analysis). ACT significantly (p < 0.001) scavenged DEN-induced reactive oxygen species (ROS) levels and prevented mitochondrial membrane potential (MMP) loss. Immunoblotting showed ACT treatment reversed DEN-induced NF-κB, Bax, Cytochrome C, Bcl-2, and Stat-3 levels. We conclude that chemoprotective effect of ACT is mediated by STAT-3 dependent regulation of oxidative stress and apoptosis and ACT has potential to be developed as a chemopreventive agent. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 782-798, 2016.

Cobalt chloride exposure dose-dependently induced hepatotoxicity through enhancement of cyclooxygenase-2 (COX-2)/B-cell associated protein X (BAX) signaling and genotoxicity in Wistar rats

“…Together, this might have potentially contributed to the genotoxic effect of CoCl 2 . The involvement of oxidative stress, inflammation, and apoptosis and their relationship with genotoxicity has been reported elsewhere . However, prolonged oxidative stress can lead to chronic inflammation which in turn might serve as a link to some chronic diseases such as cancer, diabetes and cardiovascular diseases.…”

Lachnospiraceae shift in the microbial community of mice faecal sample effects on water immersion restraint stress

“…Water immersion restraint stress (WIRS) is one of the most widely used models to discover gastric mucosal damage in animals (Jaggi et al 2011) Stress response occurs via the hypothalamic–pituitary–adrenal axis and the sympathetic-adrenal system (Ohta et al 2009). Serum levels of CORT, IL-17 and IFN-γ increase after stress treatment (Blossom et al 2016; Guo et al 2009; Peerzada et al 2016). Studies show that stress causes gastrointestinal disorders, such as irritable bowel syndrome (Ohta et al 2009).…”

Effect of verbascoside on apoptosis and metastasis in human oral squamous cell carcinoma

“…Previously, numerous studies have shown that VB effectively increases cancer cell apoptosis. For instance, VB promotes apoptosis by activating the HIPK2–p53 signaling pathway in colorectal cancer cells, exerts a tumor‐suppressive function by inducing apoptosis in human immortalized myelogenous leukemia and suppresses tumorigenicity through pro‐apoptosis in hepatocellular carcinoma cells . However, the literature on VB's anticancer activity toward different tumor types has not been sufficiently considered .…”

“…For instance, VB promotes apoptosis by activating the HIPK2-p53 signaling pathway in colorectal cancer cells, 10 exerts a tumorsuppressive function by inducing apoptosis in human immortalized myelogenous leukemia 15 and suppresses tumorigenicity through pro-apoptosis in hepatocellular carcinoma cells. 5 However, the literature on VB's anticancer activity toward different tumor types has not been sufficiently considered. 10,11,35 Our results further demonstrated that VB inhibited cell growth and promoted cell apoptosis in OSCC in vitro and in vivo.…”

“…Verbascoside (VB) is a well‐studied phenylethanoid glycoside found in several plant species. A number of studies indicate that VB exhibits anti‐oxidative, anti‐inflammatory, anti‐bacterial and anti‐fungal properties . Moreover, VB has been shown to possess anti‐tumor activity in the treatment of colorectal cancer, leukemia, gastric carcinoma and breast adenocarcinoma .…”