Abstract
BackgroundThe green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC). For most BTC patients only palliative therapy is possible, leading to a median survival of about one year. Chemoresistance is a major problem that contributes to the high mortality rates of BTC. The aim of this study was to investigate the cytotoxic effect of EGCG alone or in combination with cisplatin on eight BTC cell lines and to investigate the cellular anti-cancer mechanisms of EGCG.MethodsThe effect of EGCG treatment alone or in combination with the standard chemotherapeutic cisplatin on cell viability was analyzed in eight BTC cell lines. Additionally, we analyzed the effects of EGCG on caspase activity, cell cycle distribution and gene expression in the BTC cell line TFK-1.ResultsEGCG significantly reduced cell viability in all eight BTC cell lines (p < 0.05 or p < 0.01, respectively, for most cell lines and EGCG concentrations > 5 μM). Combined EGCG and cisplatin treatment showed a synergistic cytotoxic effect in five cell lines and an antagonistic effect in two cell lines. Furthermore, EGCG reduced the mRNA levels of various cell cycle-related genes, while increasing the expression of the cell cycle inhibitor p21 and the apoptosis-related death receptor 5 (p < 0.05). This observation was accompanied by an increase in caspase activity and cells in the sub-G1 phase of the cell cycle, indicating induction of apoptosis. EGCG also induced a down-regulation of expression of stem cell-related genes and genes that are associated with an aggressive clinical character of the tumor, such as cd133 and abcg2.ConclusionsEGCG shows various anti-cancer effects in BTC cell lines and might therefore be a potential anticancer drug for future studies in BTC. Additionally, EGCG displays a synergistic cytotoxic effect with cisplatin in most tested BTC cell lines.Graphical abstractSummary illustration
Highlights
The green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC)
Gene expression In a last step we investigated the effect of EGCG treatment on the expression of cell cycle- and apoptosis-related genes, genes that play a role in a potential cancer stem cell (CSC) phenotype and multidrug resistance, as well as genes that are related to general enhanced aggressiveness of BTC: EGCG reduced the expression of ccna2, ccnb1, ccnd1 and e2f1, but not of ccne1 in TFK-1 cells
In our study we investigated the effect of EGCG treatment alone and in combination with the standard chemotherapeutic cisplatin on the viability of eight different BTC cell lines
Summary
The green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC). For most BTC patients only palliative therapy is possible, leading to a median survival of about one year. Chemoresistance is a major problem that contributes to the high mortality rates of BTC. The aim of this study was to investigate the cytotoxic effect of EGCG alone or in combination with cisplatin on eight BTC cell lines and to investigate the cellular anti-cancer mechanisms of EGCG. The prognosis for BTC remains very poor with a five year survival rate of only 10 % [1]. Palliative chemotherapeutic therapy with cisplatin and gemcitabine achieves an average survival of about one year [1, 2]. High recurrence rates, the lack of suitable follow-up therapies and fast development of chemoresistance impede significant therapeutic success [3]. New therapeutic approaches that inhibit BTC tumorigenesis and that may overcome or even reverse the chemoresistance of BTC cells are needed
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