You can manage bookmarks using lists, please log in to your user account for this.
Media type:
E-Article
Title:
Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 in hepatocellular carcinoma
Contributor:
Kirstein, Martha M.;
Boukouris, Aristeidis E.;
Pothiraju, Deepika;
Buitrago‐Molina, Laura E.;
Marhenke, Silke;
Schütt, Jutta;
Orlik, Johanna;
Kühnel, Florian;
Hegermann, Jan;
Manns, Michael P.;
Vogel, Arndt
imprint:
Wiley, 2013
Published in:Liver International
Language:
English
DOI:
10.1111/liv.12126
ISSN:
1478-3223;
1478-3231
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide with only few therapeutic options for patients with advanced disease. There is growing evidence indicating that activation of the PI3K/Akt/<jats:styled-content style="fixed-case">mTOR</jats:styled-content> pathway plays an important role in HCC and therefore represents a promising target for novel therapeutic approaches. The aim of this study was to evaluate and compare the antitumour activity of the <jats:styled-content style="fixed-case">mTOR</jats:styled-content> inhibitor RAD001, the dual <jats:styled-content style="fixed-case">mTOR</jats:styled-content> and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Experimental Design</jats:title><jats:p>The antitumour effects of <jats:styled-content style="fixed-case">RAD</jats:styled-content>001, <jats:styled-content style="fixed-case">BEZ</jats:styled-content>235 and <jats:styled-content style="fixed-case">BKM</jats:styled-content>120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5‐Flourouracil <jats:italic>in vitro</jats:italic> and in xenografts. Cell‐cycle progression, apoptosis, and autophagy were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Treatment with <jats:styled-content style="fixed-case">RAD</jats:styled-content>001, <jats:styled-content style="fixed-case">BEZ</jats:styled-content>235 and <jats:styled-content style="fixed-case">BKM</jats:styled-content>120 markedly reduced tumour cell viability. Combination of <jats:styled-content style="fixed-case">PI</jats:styled-content>3K inhibitors with chemotherapy was most effective. <jats:styled-content style="fixed-case">RAD</jats:styled-content>001, <jats:styled-content style="fixed-case">BEZ</jats:styled-content>235 and <jats:styled-content style="fixed-case">BKM</jats:styled-content>120 reduced tumour growth mainly by inhibiting cell‐cycle progression rather than by inducing apoptosis. Interestingly, the antitumour effects were strongly associated with a reduction of mitochondrial respiration. <jats:styled-content style="fixed-case">BKM</jats:styled-content>120, which exhibited the strongest antiproliferative effect, most strongly impaired oxidative phosphorylation compared with the other drugs.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In this study, BKM120 showed the strongest antitumour activity. Our findings suggest impairment of mitochondrial function as a relevant mechanism of BKM120. Moreover, combination of PI3K and <jats:styled-content style="fixed-case">mTOR</jats:styled-content> inhibitors with cytotoxic agents could be promising option for non‐cirrhotic HCC patients.</jats:p></jats:sec>