In:
Liver International, Wiley, Vol. 33, No. 5 ( 2013-05), p. 780-793
Abstract:
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/ mTOR 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 mTOR inhibitor RAD001, the dual mTOR and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 in vitro and in vivo . Experimental Design The antitumour effects of RAD 001, BEZ 235 and BKM 120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5‐Flourouracil in vitro and in xenografts. Cell‐cycle progression, apoptosis, and autophagy were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed. Results Treatment with RAD 001, BEZ 235 and BKM 120 markedly reduced tumour cell viability. Combination of PI 3K inhibitors with chemotherapy was most effective. RAD 001, BEZ 235 and BKM 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. BKM 120, which exhibited the strongest antiproliferative effect, most strongly impaired oxidative phosphorylation compared with the other drugs. Conclusions 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 mTOR inhibitors with cytotoxic agents could be promising option for non‐cirrhotic HCC patients.
Type of Medium:
Online Resource
ISSN:
1478-3223
,
1478-3231
DOI:
10.1111/liv.2013.33.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2102783-3
detail.hit.zdb_id:
2124684-1
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