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Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma

Zhong-jie Li1, Hui-qi Dai2, Xiao-wei Huang2, Ji Feng2, Jing-huan Deng3, Zi-xuan Wang2, Xiao-mei Yang1, Yu-jia Liu1, Yong Wu2, Pan-hong Chen1, Huan Shi1, Ji-gang Wang2,4,5, Jing Zhou1, Guo-dong Lu1,2,3,6,7
1 Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
2 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China
3 Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
4 Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
5 Shenzhen People’s Hospital, Shenzhen 518020, China
6 Key Laboratory of High-incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education of China, Nanning 530021, China
7 Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore
Correspondence to: Ji-gang Wang: jgwang@icmm.ac.cn, Jing Zhou: gardenia_zhou@hotmail.com, Guo-dong Lu: golden_lu@hotmail.com,
DOI: 10.1038/s41401-020-0478-3
Received: 19 March 2020
Accepted: 6 July 2020
Advance online: 22 July 2020

Abstract

Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.
Keywords: Sorafenib; Artesunate; HCC; Ferroptosis; Mitochondria; Lysosome

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