Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1α expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells.
Cumulative evidence has established that hypoxia-inducible factor-1α (HIF-1α) 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-1α by Q39 resulted in a drastic decrease in VEGF expression. These results indicate that Q39 is an effective inhibitor of HIF-1α and provide new perspectives into the mechanism of its anticancer activity. Interestingly, neither the HIF-1α degradation rate nor the HIF-1α steady-state mRNA level was affected by Q39. Instead, suppression of HIF-1α accumulation by Q39 correlated with prominent dephosphorylation of mTOR and 4E-BP1, a pathway known to regulate protein expression at the translational level.
Weng
Qinjie
Q
Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Rd., Hangzhou, Zhejiang, 310058, China.
Zhang
Jun
J
Cao
Ji
J
Xia
Qing
Q
Wang
Duoduo
D
Hu
Yongzhou
Y
Sheng
Rong
R
Wu
Honghai
H
Zhu
Difeng
D
Zhu
Hong
H
He
Qiaojun
Q
Yang
Bo
B
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics
C528740:3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline-1,4-dioxide; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D011810:Quinoxalines; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases