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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

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Summary

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.

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Abbreviations

HIF-1:

hypoxia inducible factor-1

VEGF:

vascular endothelial growth factor

Akt:

oncogene from AKR mouse thymoma

4E-BP1:

initiation factor 4E-binding protein 1

mTOR:

mammalian target of rapamycin

p70S6K:

p70 S6 kinase

PI3K:

phosphoinositide 3-kinase

eIF4E:

eukaryotic translation initiation factor 4E

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Acknowledgments

This work was supported by The National Natural Science Foundation (No. 30873096 and 20602030), Zhejiang Provincial Natural Science Foundation (No. R2080326 and Z2090053), and Education Department Foundation of Zhejiang Province (No. 20070166 and No. 20080116). We also extend our heartfelt thanks to Dr. Huijun Zhou and Jiali Zhang for their help.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Rd., Hangzhou, Zhejiang, 310058, China

    Qinjie Weng, Jun Zhang, Ji Cao, Duoduo Wang, Honghai Wu, Difeng Zhu, Hong Zhu, Qiaojun He & Bo Yang

  2. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hangzhou, China

    Qing Xia, Yongzhou Hu & Rong Sheng

Authors
  1. Qinjie Weng
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  2. Jun Zhang
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  3. Ji Cao
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  4. Qing Xia
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  9. Difeng Zhu
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  10. Hong Zhu
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  11. Qiaojun He
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  12. Bo Yang
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Corresponding authors

Correspondence to Qiaojun He or Bo Yang.

Additional information

Qinjie Weng and Jun Zhang contributed equally to this work.

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Figure S1

Q39 exhibits potential antiangiogenic activity. Inhibition of angiogenesis was determined using the CAM assay. The sterile filter paper square saturated with Q39 (2 and 8 μg), TPT (as a positive control) or physiological saline solution was placed in areas between vessels but never onto any large vessels. After 48 h, the CAMs were carefully isolated and were fixed in methanol/acetone. Results of the samples were photographed (PDF 29 kb)

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Weng, Q., Zhang, J., Cao, J. et al. 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. Invest New Drugs 29, 1177–1187 (2011). https://doi.org/10.1007/s10637-010-9462-y

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