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Modulation of copper transporters in protection against cisplatin-induced cochlear hair cell damage

Journal of Otology 2011年第2期6卷 51-59页

作者： Richard Salvi Center for Hearing and Deafness Department of Communicative Disorders and SciencesState University of New York at Buffalo137 Cary Hall3435 Main StreetBuffaloNY 14214 USA

Cisplatin belongs to platinum-based drugs and is widely used in cancer *** is one of the major dose limiting side-effects of *** toxicity to occur cisplatin must first be transported from the bloodstream into cochlear *** copper transporters are considered pathways for regulating the uptake and translocation of cisplatin into cells:Ctr1,ATP7A and *** recent study with cochlear organotypic cultures shows that cochlear hair cells can be destroyed by cisplatin at low concentrations from 10μm to 100μ***,high doses of cisplatin cannot damage hair cells,maybe due to intrinsic feedback reactions that increase export of platinum by ATP7B when the platinum concentration is high in extracellular *** is a specific copper transporter inhibitor that can block the entrance of copper and platinum,and may prevent cisplatin-induced cochlear hair cell *** evaluate this hypothesis,we treated cochlear organotypic cultures with cisplatin (10 μm or 50 μm) alone,or cisplatin combined with cimitidine at concentrations ranging from 10-2000 μm for 48 *** at 10 μm damaged about 20% hair *** contrast,when cimitidine (10 μm,100 μm and 2000 μm) was added to the culture,near 100% cochlear hair cell *** higher concentration (50 μm),cisplatin destroyed about 80% of cochlear hair ***,100 μmcimitidine rescued about 50% hair cells from cisplatin damage,and 2000μm cimitidine protected about 80% hair *** data of western blot showed that CTR1 and ATP7B expressions were increased in cisplatin treated cochlear tissue,but cimitidine significantly reduced CTR1 and *** addition,ATP7A expression was depressed a little after cisplatin *** that Ctr1 is involved in copper and platinum influx,but the ATP7A and ATP7B are copper export transporters,the results suggest that cimitidine can effectively block the entrance by copper transporters and stop the influx of cisplatin.

关键词： cisplatin copper transporter ototoxicity cochlear hair cell

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OTOTOXIC MODEL OF OXALIPLATIN AND PROTECTION FROM NICOTINAMIDE ADENINE DINUCLEOTIDE

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Journal of Otology 2013年第1期8卷 63-71页

作者： DING Dalian JIANG Haiyan FU Yong LI Yongqi Richard Salvi Shinichi Someya Masaru Tanokura Center for Hearing and Deafness State University of New York at Buffalo Sixth People’s Hospital Shanghai Oriental Otolaryngology InstituteShanghai Jiao Tong University Xiangya Hospital Central South University Department of Applied Biological Chemistry University of Tokyo The First Officiated Hospital College of MedicineZhejiang University The Third Affiliated Hospital of Sun Yat-Sen University University of Florida

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 initial-ly 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 demon-strated 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 apop-totic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+treatment great-ly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+provides signifi-cant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply.

关键词： oxaliplatin apoptosis copper transporter nicotinamide adenine dinucleotide

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