Exp Mol Med.  2015 Feb;47(2):e142. 10.1038/emm.2014.112.

Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes

• Kim SJ
• Hur JH
• Park C
• Kim HJ
• Oh GS
• Lee JN
• Yoo SJ
• Choe SK
• So HS
• Lim DJ
• Moon SK
• Park R

• KMID: 2155407
• DOI: http://doi.org/10.1038/emm.2014.112

Abstract

Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.

MeSH Terms

Animals
Antioxidants/*metabolism/*pharmacology
Apoptosis/drug effects
Caspase 3/metabolism
Caspase 8/metabolism
Cell Line
Cisplatin/*toxicity
Cysteine/*analogs & derivatives/pharmacology
Gene Expression Regulation/*drug effects
Gene Knockdown Techniques
Glutathione/*metabolism
Heme Oxygenase-1/genetics
Intracellular Space/metabolism
Male
Metabolic Detoxication, Phase II/genetics
Mice
NF-E2-Related Factor 2/genetics
Nitric Oxide/biosynthesis
Organ of Corti/*drug effects/*metabolism
RNA Interference
Rats
Reactive Oxygen Species/metabolism
Superoxide Dismutase/genetics
Antioxidants
Caspase 3
Caspase 8
Cisplatin
Cysteine
Glutathione
Heme Oxygenase-1
NF-E2-Related Factor 2
Nitric Oxide
Reactive Oxygen Species
Superoxide Dismutase