Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma.

Abstract

BACKGROUND:

Reactive oxygen species (ROS) contribute to adult tumorigenesis; however, their roles in pediatric solid tumors are unknown. Here, we sought to define the steady-state ROS levels in neuroblastoma and to examine whether aggressive cellular behavior, which may predict treatment failure, is regulated by ROS.

METHODS:

Neuroblastoma sections were assessed for 4-hydroxynonenal (4-HNE), a marker of intracellular lipid peroxidation and a byproduct of increased levels of ROS. Human neuroblastoma cell lines, MYCN-amplified BE(2)-C and MYCN-nonamplified SK-N-SH, were examined in our study. Superoxide and hydroperoxide oxidation products were detected by staining for dihydroethidium (DHE) and 5, 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (CDCFH2), using the oxidation-insensitive analog CDCF as a negative control. Cells were treated with N-acetylcysteine (NAC; 10 mmol/L) daily for 5 days and analyzed.

RESULTS:

Greater expression of 4-HNE was observed in undifferentiated tumor sections as compared with the more differentiated tumors. Interestingly, increased levels of ROS were detected in MYCN-amplified BE(2)-C cells. Moreover, gastrin-releasing peptide receptor-induced ROS production stimulated upregulation of the hypoxia inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway and an increase in cell growth. Antioxidant NAC decreased HIF-1α/VEGF expression and inhibited BE(2)-C cell growth.

CONCLUSION:

We report a novel observation that shifting the redox balance toward greater ROS levels results in a more aggressive neuroblastoma phenotype. Our data suggest that ROS play a critical role in refractory neuroblastoma.

• Authors: Yueming Zhu, Pritha Paul, Sora Lee, Brian T Craig, Eric J Rellinger, Jingbo Qiao, David R Gius, Dai H Chung
• Journal: Surgery (Surgery) Vol. 158 Issue 3 Pg. 827-36 (Sep 2015) ISSN: 1532-7361 [Electronic] United States
• PMID: 26088922 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Biomarkers, Tumor
• Reactive Oxygen Species
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antioxidants (pharmacology)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Immunohistochemistry
• Neuroblastoma (metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)