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Open Access Highly Accessed Research article

Triptolide induces apoptotic cell death of human cholangiocarcinoma cells through inhibition of myeloid cell leukemia-1

Xiwei Ding1, Bin Zhang1, Qingshan Pei12, Jianmei Pan3, Shuling Huang1, Yan Yang1, Zhu Zhu1, Ying Lv1* and Xiaoping Zou1*

Author Affiliations

1 Department of Gastroenterology, Drum Tower Hospital, Affiliated to Medical School of Nanjing University, Nanjing, China

2 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China

3 Department of Gastroenterology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, China

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BMC Cancer 2014, 14:271  doi:10.1186/1471-2407-14-271

Published: 17 April 2014

Abstract

Background

Cholangiocarcinoma (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.

Methods

CCK-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.

Results

Triptolide 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.

Conclusions

Triptolide has profound antitumor effect on CCA, probably by inducing apoptosis through inhibition of Mcl-1. Triptolide would be a promising therapeutic agent for CCA.

Keywords:
Triptolide; Cholangiocarcinoma; Mcl-1; Apoptosis