Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

Rong,Li‑Wen; Wang,Rui‑Xue; Zheng,Xue‑Lian; Feng,Xu‑Qin; Zhang,Lei; Zhang,Lin; Lin,Yong; Li,Zhi‑Ping; Wang,Xia

doi:10.3892/ol.2017.6059

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

Authors:
- Li‑Wen Rong
- Rui‑Xue Wang
- Xue‑Lian Zheng
- Xu‑Qin Feng
- Lei Zhang
- Lin Zhang
- Yong Lin
- Zhi‑Ping Li
- Xia Wang
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Affiliations: Laboratory of Molecular and Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: April 20, 2017 https://doi.org/10.3892/ol.2017.6059
Pages: 5028-5034

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Abstract

The small molecule multi-kinase inhibitor sorafenib has become the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC) and renal cell carcinoma. Similar to other kinase inhibitors, drug resistance hinders its clinical use; thus, combination therapy to improve sorafenib sensitivity is a promising approach. The present study shows for the first time that the combination of sorafenib and wogonin exerts a significant potentiation of cytotoxicity in a number of human HCC cell lines in a dose‑dependent manner. Enhanced cell death was due to potentiation of apoptosis, which was demonstrated by increased apoptotic cell populations, caspase activation and suppression of cell death by the pan‑caspase inhibitor carbobenzoxy‑valyl‑alanyl‑aspartyl. Sorafenib induced autophagy activation, which was shown by autophagic flux. Suppression of autophagy with the autophagy inhibitors chloroquine or 3‑methyladenine significantly enhanced cytotoxicity, suggesting that sorafenib‑induced autophagy is cytoprotective. Notably, wogonin effectively inhibited sorafenib‑induced autophagy. Altogether, our results indicate that the combination of wogonin and sorafenib effectively kills human HCC cells. This occurs, at least in part, through autophagy inhibition, which potentiates apoptosis. Thus, wogonin could be an ideal candidate for increasing sorafenib's activity in HCC therapy, which warrants further investigation in vivo.

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