Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat.
Cisplatin, a chemotherapeutic agent of choice for the treatment of solid tumors, produces hearing loss in approximately half a million new cancer patients annually in the United States. The hearing loss is due, in part, to increased generation of reactive oxygen species (ROS) in the cochlea, leading to lipid peroxidation and damage or death of outer hair cells in the organ of Corti. The cochlea expresses the transient receptor potential vanilloid 1 (TRPV1), which are normally expressed on small diameter neurons in the peripheral nervous system and mediate thermal sensitivity, but whose role in the cochlea is unclear. In this study, we show that TRPV1 is coregulated along with the NADPH oxidase isoform, NOX3, by cisplatin. Induction of these proteins by cisplatin is dependent on ROS generation, since it is reversed by systemic lipoic acid administration. In organ of Corti hair cell cultures (UB/OC-1 cells), cisplatin activates and induces TRPV1 and NOX3, leading to apoptosis of these cells. Inhibition of TRPV1 by capsazepine or ruthenium red reduced the apoptosis, implicating TRPV1 in this process. Treatment of UB/OC-1 cultures with short interfering RNA (siRNA) against either TRPV1 or NOX3 reduced cisplatin-induced apoptosis, while round window application of TRPV1 siRNA to rats reduced TRPV1 expression, decreased damage to outer hair cells and reduced cisplatin-induced hearing loss. These data provide a link between NOX3 and TRPV1 in cisplatin-induced hearing loss and suggest that targeting these proteins for knockdown by siRNA could serve as a novel approach in treating cisplatin ototoxicity.
Mukherjea
Debashree
D
Departments of Pharmacology and Surgery, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9629, USA.
Jajoo
Sarvesh
S
Whitworth
Craig
C
Bunch
Jennifer R
JR
Turner
Jeremy G
JG
Rybak
Leonard P
LP
Ramkumar
Vickram
V
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000628:therapy; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D008063:Thioctic Acid / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D007527:Isoenzymes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D008063:Thioctic Acid; D019255:NADPH Oxidases; C534192:Nox3 protein, rat; D002945:Cisplatin