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. b-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 mmol 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 b-escin) or 36 weeks (15 control, 5 b-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm b-escin significantly suppressed lung tumor (adenoma þ adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. b-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 b-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 b-escin (0-40 mmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that b-escin inhibits tobacco carcinogeninduced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling. Cancer Prev Res; 6(10);

β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability

“…Moreover, enrichment of ALDH family genes in GIC has been observed [52]. In the present study, β-escin treatment decreased the percentage of ALDH activity in GIC; consistent with previous reports that β-escin inhibits ALDH activity in H460 human lung cancer cells [39]. Furthermore, we demonstrate that treatment with TMZ alone has no effect on ALDH activity, and when co-administered with β-escin does not alter the β-escin induced decrease in ALDH positive cells.…”

“…Similar to our results in Jurkat and MOLT4 cell lines, Zhang and colleagues reported that β-escin induces apoptosis in acute leukaemia T cells via induction of the intrinsic cell death pathway [29]. In addition, β-escin has been reported to induce apoptosis in a number of cancer cell lines, including pancreatic carcinoma [38], lung adenocarcinoma [39], cholangiocarcinoma [40, 41] and gastric adenocarcinoma [42] via a reduction in cellular proliferation and induction of apoptosis. However, we did not detect any obvious action of β-escin on more differentiated human tumour cell lines in vitro ; a result, which differs from previous studies and may be due to the possible heterogeneity and percentage of tumour initiating cells in cell culture.…”

Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms

“…Since NNK activates several aberrant signaling pathways in lung carcinogenesis, compounds that can attenuate these signaling pathways, such as AKT/mTOR inhibitor rapamycin [118], RhoA/Rock inhibitor β-escin [120], NF-κB pathway inhibitor kava [126], fatty acid synthase inhibitor C93 [136], MAPK inhibitor tea polyphenols [137], and IGF-1R/IR inhibitor metformin [138], will reduce carcinogenesis in NNK-induced lung cancer animal models.…”

Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells

“…The ability of Rho GTPase family members to regulate cytoskeletal dynamics, cell adhesion, and cell migration 10) points to a central role in cancer cell invasion and metastasis. The pro-oncogenic role of RhoA has been well identified in breast cancer, 18,19) in lung cancer, 20,21) and has been rarely determined in CC. 22) The migration enhancement of CC cells by erythropoietin is in a Janus kinase-and RhoA-dependent manner.…”