Abstract
Sorafenib is currently the standard chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC). But its efficacy requires improvement, it is imperative to seek therapeutic strategies that combine sorafenib with other anticancer agents. In this study we investigated the synergistic anticancer effect of combining sorafenib and artesunate, an anti-malaria drug derivative, against HCC in vitro and in vivo. We first showed that artesunate (1-100 μM) alone dose-dependently inhibited the proliferation of five HCC cell lines tested with IC50 values of around 100 μM. Artesunate treatment dose-dependently increased the ROS level in both HuH7 and Hep3B cells; addition of NAC significantly ameliorated the antiproliferation effect of artesunate against HuH7 and Hep3B cells. Then we demonstrated that combination of sorafenib and artesunate exerted synergistic antiproliferation effect and induced synergistic apoptosis in HCC cell lines. In nude mice bearing Hep3B xenografts, combined administration of sorafenib and artesunate significantly enhanced the suppression on tumor growth. We further revealed that sorafenib dose-dependently decreased the levels of p-ERK and p-STAT3, whereas artesunate markedly increased the levels of p-ERK and p-STAT3 in HuH7 and Hep3B cells. When used in combination, sorafenib abolished artesunate-elevated levels of p-STAT3 and p-ERK. Moreover, pharmacological inhibition of ERK by inhibitor PD0325901 or STAT3 by inhibitor Stattic markedly enhanced the anticancer activity of artesunate, suggesting that suppression of ERK and STAT3 signaling by sorafenib contributes to the synergistic anticancer activity against HCC caused by combination of sorafenib and artesunate. Taken together, our results provide an evidence for possible use of sorafenib plus artesunate or artemisinin analogs for treatment of HCC in the future.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common solid cancers and a leading cause of cancer-related death worldwide [1,2,3]
Anti-HCC activity of artesunate or sorafenib We first examined the effect of artesunate or sorafenib alone on cell viability using an MTT assay
Sorafenib suppressed the growth of all five HCC cell lines in a dosedependent manner, with IC50 values of 6.1 μM (HepG2), 7.4 μM (PLC/PRF/5), 14.7 μM (HCCLM3), 3.6 μM (Hep3B), and 2.6 μM (HuH7) (Fig. 1a, left panel)
Summary
Hepatocellular carcinoma (HCC) is one of the most common solid cancers and a leading cause of cancer-related death worldwide [1,2,3]. China currently accounts for over half of the global incidence of HCC due to the high rate of chronic hepatitis B virus infection [4, 5]. HCC exhibits low sensitivity to chemotherapeutic agents, and there are currently limited drugs available for disease treatment [6, 7]. An inhibitor of the nonreceptor tyrosine kinase RAF and several receptor tyrosine kinases, is a first-line and widely used drug for the systemic treatment of advanced-stage HCC [8]. It is imperative to improve the efficacy of sorafenib for the improved treatment of HCC
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