The Histone Deacetylase Inhibitor Sodium Butyrate Protects Against Cisplatin-Induced Hearing Loss in Guinea Pigs

Authors

  • Marie Drottar,

    1. Department of Otolaryngology, Children's Hospital, Boston, Massachusetts, U.S.A.
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  • M Charles Liberman MD, PhD,

    1. Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Eaton Peabody Laboratory, MA Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.
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  • Rajiv R. Ratan PhD,

    1. Department of Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, New York, U.S.A.
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  • David W. Roberson MD

    Corresponding author
    1. Department of Otolaryngology, Children's Hospital, Boston, Massachusetts, U.S.A.
    2. Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, U.S.A.
    • Dr. David W. Roberson, Department of Otolaryngology and Communication Disorders, Children's Hospital Boston, Fegan 9, Boston, Massachusetts 02115, U.S.A.
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  • Editor's Note: This Manuscript was accepted for publication November 11, 2005.

    Supported by grants from the NIDCD: KO8 DC00152 (d.w.r.), RO1 DC0188 (m.c.l.), and P30 DC05209 (m.c.l.), the Children's Hospital Otolaryngology Foundation Research Fund, and the Michaela Madrigal Research Fund.

Abstract

Objective: There is a need for otoprotective agents that can be administered systemically without compromising cancer treatment. Histone deacetylase inhibitors are anticancer agents that act by upregulating the expression of cell-cycle control genes. They are also neuroprotective, leading us to hypothesize that they might be otoprotective. The goal of this study was to determine if the antitumor agent sodium butyrate (a histone deacetylase inhibitor) protects against cisplatin ototoxicity when administered systemically.

Study Design: This was an animal study.

Methods: Cisplatin was administered to guinea pigs who received either 12 days of sodium butyrate (7 d before and 5 d after cisplatin) or equivolume saline injections. Hearing was tested with distortion product otoacoustic emission (DPOAE) analysis before the start of the study and 2 weeks after cisplatin treatment.

Results: Guinea pigs given a single intraperitoneal injection of 14 mg/kg cisplatin experience a mean hearing loss of 8 dB across the frequencies of 3.5, 5, 7, 10, 14, and 20 kHz. Intraperitoneal injection of 1.2 mg/kg sodium butyrate per day for 7 days before and 5 days after cisplatin almost completely eliminates this threshold shift (P = .0011).

Conclusions: The histone deacetylase inhibitor sodium butyrate gives almost complete protection in a single-dose model of cisplatin ototoxicity in guinea pigs. Because histone deacetylase inhibitors are anticancer agents with very few side effects, they may be candidates for clinical use during cisplatin chemotherapy.

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