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Open Access Highly Accessed Research article

Oridonin induces apoptosis and cell cycle arrest of gallbladder cancer cells via the mitochondrial pathway

Runfa Bao12, Yijun Shu12, Xiangsong Wu12, Hao Weng12, Qian Ding12, Yang Cao12, Maolan Li12, Jiasheng Mu12, Wenguang Wu12, Qichen Ding12, Zhujun Tan12, Tianyu Liu12, Lin Jiang12, Yunping Hu12, Jianfeng Gu3* and Yingbin Liu12*

Author Affiliations

1 Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China

2 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China

3 Department of General Surgery, Changshu Hospital, Affiliated to Suzhou University, No.1 Shuyuan Road, Changshu 215500, China

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BMC Cancer 2014, 14:217  doi:10.1186/1471-2407-14-217

Published: 21 March 2014

Abstract

Background

Gallbladder cancer is the most frequent malignancy of the bile duct with high aggressive and extremely poor prognosis. The main objective of the paper was to investigate the inhibitory effects of oridonin, a diterpenoid isolated from Rabdosia rubescens, on gallbladder cancer both in vitro and in vivo and to explore the mechanisms underlying oridonin-induced apoptosis and cell cycle arrest.

Methods

The anti-tumor activity of oridonin on SGC996 and NOZ cells was assessed by the MTT and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/PI double-staining and Hoechst 33342 staining assays. Loss of mitochondrial membrane potential was observed by Rhodamine 123 staining. The in vivo efficacy of oridonin was evaluated using a NOZ xenograft model in athymic nude mice. The expression of cell cycle- and apoptosis-related proteins in vitro and in vivo was analyzed by western blot analysis. Activation of caspases (caspase-3, -8 and -9) was measured by caspases activity assay.

Results

Oridonin induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in SGC996 and NOZ cells in a dose-dependent manner. Intraperitoneal injection of oridonin (5, 10, or 15 mg/kg) for 3 weeks significantly inhibited the growth of NOZ xenografts in athymic nude mice. We demonstrated that oridonin regulated cell cycle-related proteins in response to S-phase arrest by western blot analysis. In contrast, we observed inhibition of NF-κB nuclear translocation and an increase Bax/Bcl-2 ratio accompanied by activated caspase-3, caspase-9 and PARP-1 cleavage after treatment with oridonin, which indicate that the mitochondrial pathway is involved in oridonin-mediated apoptosis.

Conclusions

Oridonin possesses potent anti-gallbladder cancer activities that correlate with regulation of the mitochondrial pathway, which is critical for apoptosis and S-phase arrest. Therefore, oridonin has potential as a novel anti-tumor therapy for the treatment of gallbladder cancer.

Keywords:
Oridonin; Gallbladder cancer; Apoptosis; Cell cycle arrest; Mitochondrial pathway