Capsaicin exerts synergistic antitumor effect with sorafenib in hepatocellular carcinoma cells through AMPK activation
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Alicia Bort1, Elena Spínola1, Nieves Rodríguez-Henche1 and Inés Díaz-Laviada1,2
1Department of Systems Biology, School of Medicine and Heath Sciences, University of Alcala, Alcalá de Henares, E-28871, Madrid, Spain
2Chemical Research Institute Andrés M. del Río (IQAR), University of Alcala, Alcalá de Henares, E-28871, Madrid, Spain
Inés Díaz-Laviada, email: [email protected]
Keywords: capsaicin, sorafenib, AMPK, Akt, hepatocellular carcinoma
Received: June 09, 2017 Accepted: August 25, 2017 Published: September 23, 2017
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.
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