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

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.

Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling

“…It has been documented that short hairpin RNA-mediated depletion of Mcl-1 enhanced the induction of cholangiocarcinoma cell apoptosis by the multikinase inhibitor BAY 43-9006 [27]. Triptolide, a bioactive ingredient extracted from the Chinese herb Tripterygium wolfordii Hook F, has been shown to cause apoptotic cell death of human cholangiocarcinoma cells through inhibition of Mcl-1 [28]. These studies indicate the important role for Mcl-1 in apoptosis resistance of cholangiocarcinoma cells.…”

CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263

“…7) by ABT-263 in both HuCCT1 and HuH28 cell lines. Previous study has shown that the natural product Triptolide, the principle bioactive ingredient of the Chinese herb Tripterygium wilfordii Hook F, inhibited growth and downregulated MCL1 expression in CCA cells 29 . The results of western blotting validated the suppression of MCL1 by Triptolide in HuCCT1 and HuH28 cells (Fig.…”

Designing a broad-spectrum integrative approach for cancer prevention and treatment

“…For instance, triptolide, a component of the Chinese herb Tripterygium wilfordii , is known to cause apoptosis in cancer cells [47]. Extracts of the herb have been used in clinical trials for a variety of inflammatory and immune-linked conditions, and have demonstrated both antiinflammatory and immune suppressant activity, raising concern for its effect on immune evasion [48,49].…”