Shikonin potentiates the effect of arsenic trioxide against human hepatocellular carcinomain vitroandin vivo

Abstract

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.

<p>Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin Through Regulating PKM2</p>

“…40 Similar reports had been reported in liver cancer. 41 The above studies provided ideas for the combination of SK and other anti-hepatocarcinoma drugs. In the present study, we evaluated the combined effects of SK and sorafenib both in vitro and in vivo experiments.…”

Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms

“…Shikonin, a natural naphthoquinone derived from the Chinese medicinal herb Lithospermum erythrorhizon, showed synergistic effect with gemcitabine, cisplatin and arsenic trioxide against pancreatic [95], colon [97] and hepatocellular [98] cancer, respectively. Song et al [28] and Liu et al [36] have also demonstrated the chemosensitizing effect of oxymatrine, one of the major components extracted from Sophora flavescens, widely used in TCM.…”

Enhanced antitumor activity of combined megestrol acetate and arsenic trioxide treatment in liver cancer cells

“…Recently, studies about ATO focused on combination treatment with other drugs, such as icariin, metformin, shikonin, sorafenib. The results showed that combined treatments with ATO potentially enhanced the antitumor effect in HCC (27)(28)(29)43,44). There was study showed that ATO induced mitochondrial apoptotic cell death by ROS increase which was potentially required for activations of p38 MAPK and JNK in human cervical cancer cells (18,28,43).…”

“…The results showed that combined treatments with ATO potentially enhanced the antitumor effect in HCC (27)(28)(29)43,44). There was study showed that ATO induced mitochondrial apoptotic cell death by ROS increase which was potentially required for activations of p38 MAPK and JNK in human cervical cancer cells (18,28,43). Notably, metformin synergized with ATO inhibited proliferation of intrahepatic cholangiocarcinoma cells potentially via promoting cell apoptosis and regulating AMPK/p38 MAPK-ERK3/mTORC1 pathways (45).…”