The histone deacetylase inhibitor sodium butyrate protects against cisplatin-induced hearing loss in guinea pigs.
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.


METHODS
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.
Department of Otolaryngology, Children's Hospital, and the Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Marie
M
Drottar
M Charles
MC
Liberman
Rajiv R
RR
Ratan
David W
DW
Roberson
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002087:Butyrates / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017084:Otoacoustic Emissions, Spontaneous
D000970:Antineoplastic Agents; D002087:Butyrates; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D051548:Histone Acetyltransferases; D002945:Cisplatin