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

Yueming Zhu, Pritha Paul, Sora Lee, Brian T. Craig, Eric J. Rellinger, Jingbo Qiao, David R. Gius, Dai H. Chung*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)827-836
Number of pages10
JournalSurgery (United States)
Volume158
Issue number3
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Surgery

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