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

Cancer Prev Res (Phila). 2013 Oct;6(10):1140-9. doi: 10.1158/1940-6207.CAPR-13-0216. Epub 2013 Aug 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenoma / metabolism
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Disease Progression
  • Escin / therapeutic use*
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism*
  • Mice
  • Neoplasm Transplantation
  • Nicotiana / adverse effects
  • Nitrosamines / adverse effects
  • Plant Extracts / chemistry
  • Real-Time Polymerase Chain Reaction
  • Retinal Dehydrogenase
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Nitrosamines
  • Plant Extracts
  • RHOA protein, human
  • Escin
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • rho-Associated Kinases
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein