Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses.
Preventive measures against oral carcinogenesis are urgently warranted to lower the high morbidity and mortality associated with this malignancy worldwide. Here, we investigated the chemopreventive efficacy of grape seed extract (GSE) and resveratrol (Res) in 4-nitroquinoline-1-oxide (4NQO)-induced tongue tumorigenesis in C57BL/6 mice. Following 8 weeks of 4NQO exposure (100 µg/ml in drinking water), mice were fed with either control AIN-76A diet or diet containing 0.2% GSE (w/w) or 0.25% Res (w/w) for 8 subsequent weeks, while continued on 4NQO. Upon termination of the study at 16 weeks, tongue tissues were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for molecular targets by immunohistochemistry. GSE and Res feeding for 8 weeks, moderately decreased the incidence, but significantly prevented the multiplicity and severity of 4NQO-induced preneoplastic and neoplastic lesions, without any apparent toxicity. In tongue tissues, both 4NQO + GSE and 4NQO + Res treatment correlated with a decreased proliferation (BrdU labeling index) but increased apoptotic death (TUNEL-positive cells) as compared to the 4NQO group. Furthermore, tongue tissues from both the 4NQO + GSE and 4NQO + Res groups showed an increase in activated metabolic regulator phospho-AMPK (Thr172) and decreased autophagy flux marker p62. Together, these findings suggest that GSE and Res could effectively prevent 4NQO-induced oral tumorigenesis through modulating AMPK activation, and thereby, inhibiting proliferation and inducing apoptosis and autophagy, as mechanisms of their efficacy.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Sangeeta
S
Shrotriya
Alpna
A
Tyagi
Gagan
G
Deep
David J
DJ
Orlicky
Joshua
J
Wisell
Xiao-Jing
XJ
Wang
Robert A
RA
Sclafani
Rajesh
R
Agarwal
Chapla
C
Agarwal
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D055372:AMP-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D056604:Grape Seed Extract / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D014059:Tongue / Q000187:drug effects / Q000473:pathology; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D056604:Grape Seed Extract; D013267:Stilbenes; D015112:4-Nitroquinoline-1-oxide; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol
AMPK; biomarkers; chemoprevention; head and neck squamous cell carcinoma; tumor progression