Capsaicin exerts synergistic antitumor effect with sorafenib inhepatocellular carcinoma cells through AMPK activation
Authors
Bort Bueno, Alicia Carmen; Spinola Lasso, Elena; Rodríguez Henche, María de las Nieves; Díaz-Laviada Marturet, Inés CeciliaIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/60382DOI: 10.18632/oncotarget.21196
ISSN: 1949-2553
Date
2017-09-23Bibliographic citation
Oncotarget, 2017, v. 8, n. 50, p. 87684-87698
Keywords
capsaicin
sorafenib
AMPK
Akt
hepatocellular carcinoma
Project
BFU2012-31444 (Spanish Ministry of Economy and Competitiveness); POII11-0159-0054 (Junta de Comunidades Castilla- LaMancha); CCG2015/BIO-035 (Alcala University); Patrocinio 2013-001 (Fundación Tatiana Pérez de Guzmán el Bueno) (
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Rights
© by the Author(s)
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
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.
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