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Acteoside‐mediates chemoprevention of experimental liver carcinogenesis through STAT‐3 regulated oxidative stress and apoptosis
Author(s) -
Peerzada Kaiser J.,
Faridi Aamir H.,
Sharma Love,
Bhardwaj Subhash C.,
Satti Naresh K.,
Shashi Bhushan,
Tasduq Sheikh A.
Publication year - 2016
Publication title -
environmental toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.813
H-Index - 77
eISSN - 1522-7278
pISSN - 1520-4081
DOI - 10.1002/tox.22089
Subject(s) - oxidative stress , apoptosis , reactive oxygen species , dna damage , carcinogen , pharmacology , genotoxicity , toxicity , chemistry , inflammation , necrosis , carcinogenesis , programmed cell death , biology , medicine , immunology , biochemistry , dna , gene , organic chemistry
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.