Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1alpha expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells.
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Weng Q, Zhang J, Cao J, Xia Q, Wang D, Hu Y, Sheng R, Wu H, Zhu D, Zhu H, He Q, Yang B
Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1alpha expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells.
Invest New Drugs. 2011 Dec;29(6):1177-87. doi: 10.1007/s10637-010-9462-y. Epub 2010 Jun 5.
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- 20524035 [ View in PubMed]
- Abstract
Cumulative evidence has established that hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in hepatocellular carcinoma angiogenesis, invasiveness and metastasis. 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39) has recently shown great antiproliferative activity in extensive cell lines in normoxia and hypoxia. In this study, Q39 exhibited high antiproliferative activity against hepatoma both in vitro and in vivo, mainly by inducing apoptosis. In addition, suppression of HIF-1alpha by Q39 resulted in a drastic decrease in VEGF expression. These results indicate that Q39 is an effective inhibitor of HIF-1alpha and provide new perspectives into the mechanism of its anticancer activity. Interestingly, neither the HIF-1alpha degradation rate nor the HIF-1alpha steady-state mRNA level was affected by Q39. Instead, suppression of HIF-1alpha accumulation by Q39 correlated with prominent dephosphorylation of mTOR and 4E-BP1, a pathway known to regulate protein expression at the translational level.