Shikonin potentiates the effect of arsenic trioxide against human hepatocellular carcinoma in vitro and in vivo
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Jingjing Song1,*, Zhongwei Zhao1,*, Xiaoxi Fan1,*, Minjiang Chen1, Xingyao Cheng2, Dengke Zhang1, Fazong Wu1, Xihui Ying1, Jiansong Ji1
1Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang University Lishui Hospital, Lishui, Zhejiang 323000, China
2Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang University Lishui Hospital, Lishui, Zhejiang 323000, China
*These authors have contributed equally to this work
Jiansong Ji, email: email@example.com
Jingjing Song, email: firstname.lastname@example.org
Keywords: arsenic trioxide, shikonin, ROS, endoplasmic reticulum stress, hepatocellular carcinoma
Received: May 27, 2016 Accepted: September 02, 2016 Published: September 15, 2016
Hepatocellular carcinoma (HCC) is a highly lethal malignancy mostly because of metastasis, recurrence and acquired resistance to conventional chemotherapy. Arsenic trioxide (ATO) is successfully used to treat hematological malignancies, and has been proven to trigger apoptosis in HCC cells. However, the phase II trial evaluating the efficacy and toxicity of ATO in patients with HCC showed that single-agent ATO is poorly active against HCC. Therefore, it is of great importance to develop effective chemosensitization agents to ATO. The aim of the present study was to determine whether shikonin (SHI), a natural product from the root of lithospermum erythrorhizon, could synergistically enhance the anti-HCC efficacy of ATO both in vitro and in vivo. We found that the combination of SHI and ATO exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cells and normal cells. By inducing intracellular oxidative stress, SHI potentiated ATO-induced DNA damage, followed by increased activation of endoplasmic reticulum stress. In addition, inhibition of ROS reversed the apoptosis induced by SHI and ATO, and recovered the activation of endoplasmic reticulum stress, which revealed the vital role of ROS in the synergism. Moreover, HepG2 xenograft tumor growth in nude mice was more effectively inhibited by combined treatment with SHI and ATO. These data suggest that the combination of SHI with ATO presents a promising therapeutic approach for the treatment of HCC.
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