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- Title
Role of the Copper Transporter, CTR1, in Platinum-Induced Ototoxicity.
- Authors
More, Swati S.; Akil, Omar; Ianculescu, Alexandra G.; Geier, Ethan G.; Lustig, Lawrence R.; Giacomini, Kathleen M.
- Abstract
The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through reverse transcriptase-PCR (RTPCR), quantitative RT-PCR, Western blot, and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear, mainly outer hair cells (OHCs), inner hair cells, stria vascularis, spiral ganglia, and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. Small interfering RNA-mediated knock-down of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16, and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited because of its ototoxic effects. The studies described in this report suggest that cisplatin-induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised.
- Subjects
PHYSIOLOGICAL effects of copper; OTOTOXICITY; PHYSIOLOGICAL effects of platinum; ANTINEOPLASTIC agents; SMALL interfering RNA
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 28, p9500
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1544-10.2010