VALPRONIC ACID IMPEDES THE DEVELOPMENT OF REFLUX-INDUCED ESOPHAGEAL CANCER IN A SURGICAL RAT MODEL
Tomoharu Miyashita*1, Daisuki Matsui1, John W. Harmon2, Tetsuo Ohta1
1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan; 2Department of Surgery, Johns Hopkins University, Baltimore, MD
Background: The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer is an area of rapidly expanding investigation. In our previous study, the nuclear expression of HDAC was observed in all of the stages of squamous carcinogenesis and adeno carcinogenesis, although not in the normal esophageal epithelium in surgical rat model (Oncol Lett 8, 758-764, 2014). For this reason, HDAC inhibitors have recently emerged as potential esophageal cancer therapeutic agents. Valproic acid (VPA) has been shown to inhibit HDACs. We evaluated the effectiveness of VPA as a chemoprevention agent in a surgical rat reflux model of esophageal cancer.
Materials and Methods: The rat reflux model was created by performing an end-to-side esophagojejunostomy in Sprague Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. VPA (Sigma-Aldrich Co., Tokyo, Japan) was dissolved in 5ml/kg saline. Beginning four weeks post surgery, all animals were administered either 300mg/kg body weight injections of VPA or equivalent injections of saline 3 days per week into the subcutaneous tissue of the back. Animals were sacrificed 40 weeks after surgery and their esophagi were examined.
Results: Forty two rats survived 40 weeks post-surgery and were included in the study. Of these, 21 were included in the control group (Figure 1a), and the remaining 21 received VPA administration (Figure 1b). While 71% (15/21) of the controls developed esophageal cancer (Figure 1c), animals administered VPA had an incidence of cancer of 24% (5/21) (p=0.002, Chi-squared) (Table 1). Barrett's metaplasia was found on 86% (18/21) of the rats in the control group (Figure 1d), but there was a protective tendency in the VPA group with 62% (13/21) of the rats displaying signs of Barrett's metaplasia (p=0.079, Chi-squared). All of the rats in the VPA and control groups developed proliferative hyperplasia.
Conclusions: VPA protected against the development of esophageal cancer in a clinically relevant surgical reflux model. Further investigation is required regarding the potential clinical use of VPA as a chemopreventive agent.
Histological findings
| Histology/Group | Control(n=21) | VPA(n=21) | p value |
| Proliferative hyperplasia | 21（100%） | 21（100%） | n.s. |
| Squamous dysplasia | 6（29%） | 5（24%） | p=0.72 |
| Barrett's metaplasia | 18（86%） | 13（62%） | p=0.079 |
| Carcinoma | 15（71％） | 5（24％） | p=0.002 |
| SCC | 6（29%） | 1（5%） | p=0.038 |
| ADC | 10（48%） | 4（19%） | p=0.049 |
| ASC | 1（5%） | 0（0%） | p=0.311 |
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