Efficacy of Azatyrosine-Phenylbutyric Hydroxamides, a Histone Deacetylase Inhibitor, on Chemotherapy-Induced Gastrointestinal Mucositis.

Po-Lin Liao,Yu-Wen Cheng,Hui-Po Wang,Shih-Hsuan Huang,Wei-Kuang Huang,Jaw-Jou Kang,Chien-Hung Hung,Chi-Hao Tsai

doi:10.3390/ijms20020249

Abstract

Gastrointestinal mucositis is a serious side effect of chemotherapy. Currently, no effective treatment exists for chemotherapy-induced mucositis, prompting the need to develop an anti-mucositis agent for use in clinics. The present study investigated whether azatyrosine-PBHA (AzP), a histone deacetylase inhibitor, has a therapeutic effect on intestinal mucosa. The results indicated that AzP did not affect the proliferation and viability of cancer cells, outcomes that are achieved by suberoylanilide hydroxamic acid (SAHA). However, AzP could decrease production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor-necrosis factor-α (TNF-α). In vivo histopathological assessment showed that AzP reduced cisplatin-induced injury to the jejunum villi and triggered weight loss in the C57BL/6 mice. Immunohistochemistry (IHC) results demonstrated that mice treated with AzP also recovered from cisplatin-induced injury to the intestinal mucosa. Mechanistic in vitro study using DAVID/KEGG enrichment analysis of microarray data and confirmation by a Western blot indicated the influence of AzP on the MEK/ERK and AKT-dependent pathway. In conclusion, the study demonstrated that AzP might regulate the MEK/ERK MAPK signaling pathway to attenuate MCP-1, TNF-α, and IL-6 production and provide opportunities for the development of new anti-inflammatory drugs targeting mucositis.

Highlights

Gastrointestinal mucositis is a frequent and severe side effect of radiotherapy and chemotherapy in cancer patients [1,2]
Western blot confirm that elevated histone acetylation (Figure from Western blot confirm that azatyrosine-phenylbutyric hydroxamides (AzP) elevated histone acetylation (Figure 3A,B)
HDAC4 activity treated with azatyrosine-phenylbutyric hydroxamides (AzP)

Summary

Introduction

Gastrointestinal mucositis is a frequent and severe side effect of radiotherapy and chemotherapy in cancer patients [1,2]. 50 to 80% of patients suffered from mucositis, with the occurrence being dependent on the type of chemotherapy; vomiting, abdominal pain, and severe diarrhea [3] were the most common symptoms experienced. A life-threatening stage may be seen in patients, and severe physical obstruction of food and water intake leads to weight loss.

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Conclusion