title: 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.
authors.affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Kaiser J
authors.initials: KJ
authors.lastname: Peerzada
authors.affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Aamir H
authors.initials: AH
authors.lastname: Faridi
authors.affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Love
authors.initials: L
authors.lastname: Sharma
authors.affiliation: Department of Pathology, Government Medical College, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Bhardwaj
authors.affiliation: Natural Products Chemistry (Plants), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Satti
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.
authors.forename: Bhushan
authors.initials: B
authors.lastname: Shashi
authors.affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Sheikh A
authors.initials: SA
authors.lastname: Tasduq
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004052:Diethylnitrosamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D005960:Glucosides / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000187:drug effects*; D059808:Polyphenols
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D016207:Cytokines; D004052:Diethylnitrosamine; D005960:Glucosides; D010636:Phenols; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C058956:acteoside; D059808:Polyphenols
keywords: acteoside; chemoprevention; diethyl nitrosamine; hepatocellular carcinoma (HCC); rat