18β-Glycyrrhetinic Acid Suppresses Cell Proliferation through Inhibiting Thromboxane Synthase in Non-Small Cell Lung Cancer

Abstract

18β-glycyrrhetinic acid (18β-GA) is a bioactive component of licorice. The anti-cancer activity of 18β-GA has been studied in many cancer types, whereas its effects in lung cancer remain largely unknown. We first showed that 18β-GA effectively suppressed cell proliferation and inhibited expression as well as activity of thromboxane synthase (TxAS) in non-small cell lung cancer (NSCLC) cells A549 and NCI-H460. In addition, the administration of 18β-GA did not have any additional inhibitory effect on the decrease of cell proliferation induced by transfection with TxAS small interference RNA (siRNA). Moreover, 18β-GA failed to inhibit cell proliferation in the immortalized human bronchial epithelial cells 16HBE-T and another NSCLC cell line NCI-H23, both of which expressed minimal level of TxAS as compared to A549 and NCI-H460. However, 18β-GA abolished the enhancement of cell proliferation induced by transfection of NCI-H23 with pCMV6-TxAS plasmid. Further study found that the activation of both extracellular signal-regulated kinase (ERK)1/2 and cyclic adenosine monophosphate response element binding protein (CREB) induced by TxAS cDNA transfection could be totally blocked by 18β-GA. Altogether, we have delineated that, through inhibiting TxAS and its initiated ERK/CREB signaling, 18β-GA suppresses NSCLC cell proliferation. Our study has highlighted the significance of 18β-GA with respect to prevention and treatment of NSCLC.

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

“…As expected, several studies showed that TxA 2 antagonist, TxAS inhibitor, or TP antagonist could inhibit cancer cell growth and induce apoptosis by increasing the ROS level, inhibiting the NF-κB pathway, increasing the nuclear p27 level, or blocking ERK/CREB signaling in lung cancer, bladder cancer, and glioblastoma [83,[85][86][87][88][89][90][91].…”

Chemopreventive Effects of Licorice and Its Components

“…Other cancers that have been reported to be sensitive to the antiproliferative effects of GA or Gc include UVB-induced skin carcinogenesis [33•], prostate cancer [34], stomach cancer and leukemia [35,36], gastric cancer [37], endometrial carcinogenesis [38], pituitary adenomas [39], and breast cancer [40]. GA was reported to suppress A549 and NCI-H460 non-small cell lung cancer (NSCLC) growth and inhibit thromboxane synthase activity [41]. It did not affect human 16HBE-T bronchial epithelial cell growth or the growth of NCI-H23 lung cancer cells, which express low levels of thromboxane synthase activity [41].…”

“…GA was reported to suppress A549 and NCI-H460 non-small cell lung cancer (NSCLC) growth and inhibit thromboxane synthase activity [41]. It did not affect human 16HBE-T bronchial epithelial cell growth or the growth of NCI-H23 lung cancer cells, which express low levels of thromboxane synthase activity [41]. GA also induced apoptosis and G1 arrest in NCI-H460 NSCLC cells as was evidenced by increased expression of cleaved poly (ADP-ribosyl) polymerase (PARP) and caspase 3, and attenuated expression of Bcl-XL, Bcl-2, cyclin D1, and cyclin E [42].…”

Effects of Glycyrrhizin in a Mouse Model of Lung Adenocarcinoma

“…Previous studies have shown that glycyrrhizin inhibits proliferation and induces apoptosis in in vitro models of lung cancer [1,3,5]. As an inhibitor of high-mobility group box 1 (HMGB1), glycyrrhizin may induce TxAS through activating toll-like receptor 4 (TLR4) and the subsequent signaling such as nuclear factor (NF)-κB [6,7].…”