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.
Keywords: ROS; arsenic trioxide; endoplasmic reticulum stress; hepatocellular carcinoma; shikonin.