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

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
Publication statusPublished - Sep 1 2015
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Surgery

Cite this