Q39, a novel synthetic Quinoxaline 1,4-Di-N-oxide compound with anti-cancer activity in hypoxia.

Abstract

Hypoxia is one of the inevitable circumstances in various tumors and results in tumor resistance to radiotherapy and chemotherapy. The present data showed that 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39), derived from Quinoxaline 1,4-Di-N-oxide, possessed high anti-cancer activity in hypoxia. Cytotoxicity assay demonstrated that Q39 is a potential and high efficient anti-cancer compound in all tested cell lines with IC50 values of 0.18+/-0.03-8.88+/-1.12 microM in hypoxia and 0.33+/-0.04-8.74+/-1.28 microM in normoxia . In the following work concerning the mechanism of Q39 in hypoxia, we confirmed that Q39 could cause the apoptosis of K562 cells in a time-dependent manner. By fluorescence stain assay, Q39-induced mitochondria membrane potential (Delta Psi m) loss was observed in K562 cells in hypoxia. Based on the western blotting, Q39 decreased the protein expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in hypoxia. The compound caused the activation of caspase-3 and subsequent cleavage of its substrate poly (ADP-ribose) polymerase (PARP) in hypoxia. Meanwhile, we found the upregulation of Bax by Q39 in K562 cells as well as the downregulation of Bcl-2. Q39 also influenced the expression of Mitogen-Activated Protein Kinase (MAPKs) and other proteins relative to mitochondria induced apoptosis. In addition, Q39-mediated apoptosis was not reversed after treatment with the JNK-specific inhibitor. In summary, the present study demonstrated Q39 was a novel compound against cancer cells in hypoxia. The mitochondrial pathway mediated by Bcl-2 protein family and MAPKs and the HIF-1 pathway might be involved in signaling Q39-induced apoptosis.

• Authors: Qinjie Weng, Duoduo Wang, Peng Guo, Liang Fang, Yongzhou Hu, Qiaojun He, Bo Yang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 581 Issue 3 Pg. 262-9 (Mar 10 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18215659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline-1,4-dioxide
• Antineoplastic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Proto-Oncogene Proteins c-bcl-2
• Quinoxalines
• Vascular Endothelial Growth Factor A
• Poly(ADP-ribose) Polymerases
• Mitogen-Activated Protein Kinases
• Caspase 3

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (drug effects, metabolism)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Gene Expression Regulation (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects, metabolism)
• Inhibitory Concentration 50
• Membrane Potential, Mitochondrial (drug effects)
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Poly(ADP-ribose) Polymerases (drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Quinoxalines (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Time Factors
• Vascular Endothelial Growth Factor A (drug effects, metabolism)