Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity.

Abstract

In our previous study, we clearly demonstrated the roles of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6, and subsequent reactive oxygen species (ROS) generation on the pathogenesis of cisplatin ototoxicity in vitro and in vivo. ROS generation in cisplatin-treated HEI-OC1 auditory cells was also correlated with changing mitochondrial membrane potential. However, the roles of NADPH oxidase in cisplatin-induced ROS generation and ototoxicity have not been fully elucidated. Herein, immunohistochemical studies demonstrated that treatment of cisplatin induced the expression of NADPH oxidase isoforms NOX-1 and NOX-4 in HEI-OC1 auditory cells. Expression of mRNA for NOX-1, NOX-4, NOXO1, NOXA1, p47(phox), and p67(phox) was also increased. Inhibition of NADPH oxidase with diphenyleniodonium chloride or apocynin abolished ROS production and the subsequent apoptotic cell death in cisplatin-treated cells. Furthermore, suppression of NOX1 and NOX4 expression by small interfering RNA transfection markedly abolished the cytotoxicity and ROS generation by cisplatin. Together, our data suggest that ROS generated, in part, through the activation of NADPH oxidase plays an essential role in cisplatin ototoxicity.

• Authors: Hyung-Jin Kim, Jeong-Han Lee, Se-Jin Kim, Gi Su Oh, Hae-Dalma Moon, Kang-Beom Kwon, Channy Park, Byung Hyun Park, Ho-Kyun Lee, Sang-Young Chung, Raekil Park, Hong-Seob So
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 11 Pg. 3933-46 (Mar 17 2010) ISSN: 1529-2401 [Electronic] United States
• PMID: 20237264 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• NADPH Oxidases
• Cisplatin

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cell Line, Transformed
• Cisplatin (administration & dosage, antagonists & inhibitors, toxicity)
• Hair Cells, Auditory, Outer (drug effects, enzymology)
• Hearing Loss (chemically induced, metabolism)
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred BALB C
• NADPH Oxidases (physiology)
• Organ Culture Techniques
• Oxidative Stress (drug effects, physiology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)