title: β-Escin inhibits NNK-induced lung adenocarcinoma and ALDH1A1 and RhoA/Rock expression in A/J mice and growth of H460 human lung cancer cells.
abstract: Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
authors: Center for Cancer Prevention and Drug Development, 975 NE 10th Street, BRC 1203, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. cv-rao@ouhsc.edu; and Jagan M.R. Patlolla, E-mail: Jagan-Patlolla@ouhsc.edu.
authors: Jagan M R
authors: JM
authors: Patlolla
authors: Li
authors: L
authors: Qian
authors: Laura
authors: L
authors: Biddick
authors: Yuting
authors: Y
authors: Zhang
authors: Dhimant
authors: D
authors: Desai
authors: Shantu
authors: S
authors: Amin
authors: Stan
authors: S
authors: Lightfoot
authors: Chinthalapally V
authors: CV
authors: Rao
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D018450:Disease Progression; D004928:Escin / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009602:Nitrosamines / Q000009:adverse effects; D010936:Plant Extracts / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D050697:Retinal Dehydrogenase; D014026:Nicotiana / Q000009:adverse effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D009602:Nitrosamines; D010936:Plant Extracts; C066737:RHOA protein, human; D004928:Escin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein