Ototoxic Model of Oxaliplatin and Protection from Nicotinamide Adenine Dinucleotide

Abstract

Oxaliplatin, an anticancer drug commonly used to treat colorectal cancer and other tumors, has a number of serious side effects, most notably neuropathy and ototoxicity. To gain insights into its ototoxic profile, oxaliplatin was applied to rat cochlear organ cultures. Consistent with it neurotoxic propensity, oxaliplatin selectively damaged nerve fibers at a very low dose 1 μM. In contrast, the dose required to damage hair cells and spiral ganglion neurons was 50 fold higher (50 μM). Oxailiplatin-induced cochlear lesions initially increased with dose, but unexpectedly decreased at very high doses. This non-linear dose response could be related to depressed oxaliplatin uptake via active transport mechanisms. Previous studies have demonstrated that axonal degeneration involves biologically active processes which can be greatly attenuated by nicotinamide adenine dinucleotide (NAD+). To determine if NAD+ would protect spiral ganglion axons and the hair cells from oxaliplatin damage, cochlear cultures were treated with oxaliplatin alone at doses of 10 μM or 50 μM respectively as controls or combined with 20 mM NAD+. Treatment with 10 μM oxaliplatin for 48 hours resulted in minor damage to auditory nerve fibers, but spared cochlear hair cells. However, when cochlear cultures were treated with 10 μM oxaliplatin plus 20 mM NAD+, most auditory nerve fibers were intact. 50 μM oxaliplatin destroyed most of spiral ganglion neurons and cochlear hair cells with apoptotic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+ treatment greatly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+ provides significant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply.

Low, but Not High, Doses of Cisplatin Damage Cochlear Hair Cells in C57 Mouse Organotypic Cultures

“…Our results suggest that a peak concentration of cisplatin induces the most severe damage to hair cells, and that hair cells are able to resist damage at higher concentrations which coincides with the reports performed on rats and chinchilla [14,24,25,26]. This unexpected finding may be related to the mechanism of cisplatin resistance, which involves transport of the compound into cells.…”

Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents

“…Despite some reports of isolated instances of oxaliplatin-induced hearing loss (Guvenc et al 2016 ; Oh et al 2013 ), oxaliplatin is considered non-ototoxic in humans (Pasetto et al 2006 ; Yuce et al 2014 ). When oxaliplatin is applied directly to rat organ of Corti cultures, the observed cochlear damage is comparable with that caused by cisplatin (Dammeyer et al 2014 ; Dalian et al 2013 ), suggesting that oxaliplatin may not cross the blood-labyrinth barrier and may therefore be excluded from the cochlea when administered systemically (Hellberg et al 2009 ).…”