Short Interfering RNA against Transient Receptor Potential Vanilloid 1 Attenuates Cisplatin-Induced Hearing Loss in the Rat

Abstract

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.

Transtympanic Administration of Short Interfering (si)RNA for the NOX3 Isoform of NADPH Oxidase Protects Against Cisplatin-Induced Hearing Loss in the Rat

“…siRNA against TRPV1 applied to the round window after surgical exposure decreased both KIM-1 and NOX3 expression both in vitro and in vivo (21). In the present study, we observed that siRNA against NOX3 abrogated the upregulation of TRPV1 mRNA by cisplatin.…”

“…NOX3 appears to manifest some of its cytotoxicity through activation and induction of transient receptor potential vanilloid 1 (TRPV1) channel. Accordingly, round window administration of short interfering (si) RNA against TRPV1 reduces cisplatin-mediated ROS generation and ototoxicity (21). This latter finding suggests the existence of a feedback regulation of NOX3 activity by TRPV1.…”

“…Since ROS controls a number of genes implicated in cisplatin ototoxicity, knockdown of NOX3 would directly contribute to reduced expression of these genes which could further contribute to otoprotection. As such, knockdown of NOX3 could afford protection by not only reducing ROS generation but also by reducing TRPV1 expression, a protein which is also dependent on ROS that contributes to cisplatin ototoxicity (21).…”

Inner ear supporting cells protect hair cells by secreting HSP70

“…Hair cells are damaged by a variety of stresses including aging, noise trauma, genetic mutations, and exposure to certain therapeutic drugs, including aminoglycoside antibiotics and the antineoplastic agent cisplatin. Hair cell death caused by exposure to ototoxic drugs is a significant health problem that results in hearing loss for an estimated 500,000 Americans each year (2). Aminoglycoside antibiotics remain among the most commonly used antibiotics worldwide, and significant hearing loss or balance impairment (or both) occurs in up to 20% of patients receiving these drugs (3).…”

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

“…One of the dose-limiting side effects of cisplatin is ototoxicity, which manifests as tinnitus and/or bilateral sensorineural hearing loss in the clinical setting. [1][2][3][4] Ototoxicity caused by cisplatin has effects on a number of inner ear structures, including the stria vascularis, supporting cells, spiral ganglion cells, and outer hair cells (OHCs). 2,5,6 However, the OHCs appear to be the most susceptible to damage.…”