Abstract
Objective:To investigate the anti-tumor effect of licochalcone A (LCA) on proliferation and migration in cholangiocarcinoma (CCA) cells and to elucidate their underlying mechanisms. Methods:Human CCA cells, KKU-100, KKU-213, KKU-214, KKU-156, and KKU-452 were used to study effect of LCA on proliferation and migration by a cytotoxicity assay, wound healing assay. Reactive oxygen species levels were evaluated using DHE-fluorescent probes. Proteins associated with cancer survival and progression were analyzed by immune blotting assay. Results:LCA suppressed proliferation and induced cell death in CCA cells including KKU-100, KKU-213, KKU-214, KKU-156, and KKU-452. The CCAs cells were suppressed in association with LCA-induced accumulation of intracellular reactive oxygen species (ROS). Increased formation of ROS was causally related with suppression of Nrf2 and its down-stream antioxidant and cytoprotective enzymes. These effects may lead to the expression of Bax and release of cytochrome c and ensuring cell death. Interestingly, LCA could also inhibit cell migration and cell cycle arrest at low concentrations. These effects were associated with down-regulation of NF-kB, STAT3 and their down-stream proteins, cyclin D1, VEGF, and ICAM-1. Conclusions:These results suggest that LCA has potential therapeutic activity in suppression of CCA cells.
Highlights
Biliary duct cancer or cholangiocarcinoma (CCA) is a rare and lethal cancer where the incidence is increasing worldwide
Incidence of CCA varies widely according to geographical regions, suggesting the impact of different sets of major risk factors including chronic infection of Opisthorchis spp and Clonorchis spp, primary sclerosing cholangitis, hepatolithiasis, hepatitis and life styles (Tyson and El-Serag, 2011)
Licochalcone A suppresses cholangiocarcinoma cells viability and proliferation Licochalcone A (LCA) is a chalcone compound extracted from roots of Glycyrrhiza spp. or licorice (Figure 1a)
Summary
Biliary duct cancer or cholangiocarcinoma (CCA) is a rare and lethal cancer where the incidence is increasing worldwide. CCA is found frequently in some regions in the world, including Southeast Asia countries, and South China (Zabron et al, 2013). Incidence of CCA varies widely according to geographical regions, suggesting the impact of different sets of major risk factors including chronic infection of Opisthorchis spp and Clonorchis spp, primary sclerosing cholangitis, hepatolithiasis, hepatitis and life styles (Tyson and El-Serag, 2011). Liver fluke infection is a major risk factor of CCA in the endemic area of liver fluke in Southeast Asian countries, South China and Korea (Khan et al, 2019). In non-endemic area of liver fluke infection, other factors may contribute to the risk of CCA. Treatment options for cholangiocarcinoma including surgical resection, radiation therapy, and chemotherapy. Most of CCA patients are diagnosed at the late stage of the disease when chemotherapy mostly becomes the only option for the patients. Drug treatment does provide only a modest survival benefit, because of the development of resistance (Banales et al, 2020)
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