Abstract
Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.
Highlights
Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from the epithelial cells of the intra- and extra-hepatic bile ducts and gallbladder
No obvious reduction in cell number was observed in GW4064 or chenodesoxycholic acid (CDCA) treated group, while co-treatment with CDDP led to a significant reduction in cell viability at 48 h, compared to CDDP treatment only (Figure 1D, 1E, 1F, 1G)
We investigated whether the effect of CDDP/farnesoid X receptor (FXR) agonist on signal transducer and activator of transcription 3 (STAT3) phosphorylation in BTC cells was due to regulation of small heterodimer partner (SHP) expression
Summary
Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from the epithelial cells of the intra- and extra-hepatic bile ducts and gallbladder. The majority of BTC patients exhibit an unresectable disease at the time of diagnosis due to the advanced cancer stage. Cisplatin (CDDP) is a first line chemotherapeutic drug to treat various types of human cancers including BTCs. CDDP resistance is common in patients with BTCs. Cytotoxicity of CDDP is mediated by its interaction with DNA and the formation of DNA adducts (mainly intrastrand crosslinks), activating several signal transduction pathways and culminating in the activation of apoptosis [1]. The combination of small molecular compounds with anticancer drugs aimed at bringing tumor cell populations into a state more susceptible to the cytotoxic effects of chemotherapeutic agents is a interesting strategy in cancer chemotherapy [2, 3]. In order to improve the therapeutic efficacy of CDDP to BTC, new agents that can enhance CDDP induced apoptosis need to be identified
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