1. ¹Department of Otorhinolaryngology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
2. ²Department of Experimental Radiology and Health Physics, Faculty of Medical Science, University of Fukui, Matsuoka, Fukui 910-1193, Japan

Correspondence: N Narita, E-mail: norihiko@fmsrsa.fukui-med.ac.jp

Received 20 January 2005; Revised 3 May 2005; Accepted 25 May 2005; Published online 25 July 2005.

Abstract

To elucidate the molecular mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 44°C for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcription–polymerase chain reaction (RT–PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 44°C for 30 min at pH 6.7. Although the cytotoxicity of heating at 44°C for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G₂/M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G₂/M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43°C for 30 min in vivo. Analyses of p65 activity suggested that NF-B is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.