Abstract
In this study, we investigated the antitumoral effects of combined treatment using sorafenib and capsaicin in hepatocellular carcinoma (HCC) cells. Here we showed that the combination of the two drugs had a much stronger inhibitory effect on both HepG2 and Huh-7 human HCC cells growth than either drug alone. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. In the combination treatment using capsaicin and sorafenib, increased apoptosis, followed by the activation of caspase-9 and PARP, was observed. In addition, the present study demonstrated that sorafenib treatment induces activation of Akt, probably as a mechanism of resistance, whereas capsaicin inhibits Akt providing a possible pathway whereby capsaicin sensitizes to sorafenib in HCC cells. Moreover, capsaicin singly and the combination of capsaicin and sorafenib induce AMPK activation and Acetyl CoA carboxylase phosphorylation in HCC cells. Knocking down of AMPK by selective siRNA abrogates capsaicin-induced Akt inhibition, suggesting the involvement of AMPK in the antiproliferative effect. In vivo experiments further showed that that the anti-tumor effect of sorafenib was enhanced by its combination with 2.5 mg/Kg of capsaicin. Overall, these results show that combined treatment with capsaicin and sorafenib might improve sorafenib sensitivity and therefore it represents a promising and attractive strategy for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is a highly aggressive solid malignancy and the third cause of cancer related deaths [1]
Capsaicin and sorafenib exert a synergistic cytotoxic effect on hepatocellular carcinoma (HCC) cells To examine the effect of capsaicin and sorafenib on HCC cell proliferation, MTT cell viability assays were carried out using HepG2 and Huh-7 cells
Sorafenib and capsaicin synergistically inhibit the growth of HCC tumors in vivo To validate the synergism between capsaicin and sorafenib observed in HCC cells, we evaluated the antitumoral effect of the compounds alone or in combination in a mouse xenograft model of HCC generated by inoculation of HepG2 or Huh-7 cell lines
Summary
Hepatocellular carcinoma (HCC) is a highly aggressive solid malignancy and the third cause of cancer related deaths [1]. In spite of well-established monitoring programs in patients with risk, most tumors are diagnosed at intermediate-advanced stage, and only palliative measured can be applied. Current treatments applicable at early stages of tumor development include tumor resection, liver transplantation and chemoembolization. The only approved systemic treatment for advanced HCC is sorafenib, a multi-kinase inhibitor that targets c-Raf, B-Raf and VEGF receptor, among others. Despite the overall survival increase and the better outcome that have been obtained with sorafenib treatment [4], many patients have to adopt dose reduction or terminate the use of sorafenib because of adverse effects such as hand-foot syndrome [5], bleeding of gastrointestinal tract [4, 6] or effects on liver function. In addition acquired resistance develops more often than desired [7]
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