Abstract
BackgroundCholangiocarcinoma (CCA), a devastating neoplasm, is highly resistant to current chemotherapies. CCA cells frequently overexpress the antiapoptotic protein myeloid cell leukemia-1(Mcl-1), which is responsible for its extraordinary ability to evade cell death. Triptolide, a bioactive ingredient extracted from Chinese medicinal plant, has been shown to inhibit cell proliferation and induce apoptosis in several cancers.MethodsCCK-8 assay was performed to detect cell survival rate in vitro. DAPI staining and Flow cytometry were used to analyze apoptosis. Western blot was performed to determine the expression levels of caspase-3, caspase-7, caspase-9, PARP, and Mcl-1. Quantitative real-time PCR and immunofluorescence were used to detect the expression levels of Mcl-1. The nude mice xenograft model was used to evaluate the antitumor effect of triptolide in vivo.ResultsTriptolide reduced cell viability in cholangiocarcinoma cell lines in a dose- and time-dependent manner, with IC50 values of 12.6 ± 0.6 nM, 20.5 ± 4.2 nM, and 18.5 ± 0.7 nM at 48 h for HuCCT1, QBC939, and FRH0201 respectively. Triptolide induced apoptosis in CCA cell lines in part through mitochondrial pathway. Using quantitative real-time PCR, western blot and immunofluorescence, we have shown that triptolide downregulates Mcl-1 mRNA and protein levels. Furthermore, triptolide inhibited the CCA growth in vivo.ConclusionsTriptolide has profound antitumor effect on CCA, probably by inducing apoptosis through inhibition of Mcl-1. Triptolide would be a promising therapeutic agent for CCA.
Highlights
Cholangiocarcinoma (CCA), a devastating neoplasm, is highly resistant to current chemotherapies
The effect of triptolide on CCA cell viability We evaluated the effect of triptolide on three CCA cell lines: HuCCT1, QBC939, and FRH0201
Triptolide induces apoptosis in CCA cells To elucidate the mechanism by which triptolide causes cell death in CCA cells, we used DAPI staining and Annexin V-FITC assay to evaluate whether triptolide could induce apoptosis in CCA cells
Summary
Cholangiocarcinoma (CCA), a devastating neoplasm, is highly resistant to current chemotherapies. Triptolide, a bioactive ingredient extracted from Chinese medicinal plant, has been shown to inhibit cell proliferation and induce apoptosis in several cancers. Cholangiocarcinoma (CCA) is a highly malignant adenocarcinoma arising from the bile duct epithelial cells. The overall incidence and mortality rates of this fatal neoplasm appear to be increasing in several western countries [1,2,3,4,5]. CCA is characterized by a poor prognosis and overall low survival rates [6]. Surgical resection and liver transplantation are considered the only two potentially curative therapies. Majority of patients have advanced disease at the time of diagnosis and miss the optimal time for these curative treatment options.
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