Oncotarget

Research Papers:

Oridonin synergistically enhances JQ1-triggered apoptosis in hepatocellular cancer cells through mitochondrial pathway

Hua-Peng Zhang, Gong-Quan Li, Wen-Zhi Guo, Guang-Hui Chen, Hong-Wei Tang, Bing Yan, Jie Li, Jia-Kai Zhang, Pei-Hao Wen, Zhi-Hui Wang, Jian-Feng Lv and Shui-Jun Zhang _

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Oncotarget. 2017; 8:106833-106843. https://doi.org/10.18632/oncotarget.21880

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Abstract

Hua-Peng Zhang1,2,3,*, Gong-Quan Li1,2,3,*, Wen-Zhi Guo1,2,3, Guang-Hui Chen1,2, Hong-Wei Tang2,3, Bing Yan2,3, Jie Li1,2,3, Jia-Kai Zhang1, Pei-Hao Wen1, Zhi-Hui Wang1, Jian-Feng Lv2 and Shui-Jun Zhang1,2,3

1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

2Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

3Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, China

*These authors have contributed equally to this work

Correspondence to:

Shui-Jun Zhang, email: [email protected]

Jian-Feng Lv, email: [email protected]

Keywords: JQ1, Oridonin, HCC, Apoptosis, Bcl-2

Received: July 03, 2017     Accepted: September 21, 2017     Published: October 16, 2017

ABSTRACT

Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of cancer. However, many solid cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with Oridonin, a bioactive molecules derived from Traditional Chinese Medicine in hepatocellular carcinoma (HCC) cells. Our results showed that Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC cancer stem-like cells. Moreover, Oridonin dose-dependently inhibited the expression of several anti-apoptotic proteins, such as Bcl-2, Mcl-1, and x-linked inhibitor of apoptosis (xIAP) in HCC cells. Cell fractionation and western blotting analysis showed that the enhancement of apoptosis by Oridonin was associated with cytochrome c release, activation of caspase-9, -3 and cleavage of PARP, indicating the activation of mitochondrial apoptosis pathway. Altogether, our findings demonstrate that Oridonin may be used to effectively enhance the sensitivity of BET inhibitors in HCC therapy via downregulation of the expression of multiple anti-apoptotic proteins.


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