Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
Int J Mol Sci. 2019 Jan 10;20(2):249. doi: 10.3390/ijms20020249.
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.
胃肠道黏膜炎是化疗的一种严重副作用。目前，针对化疗引起的黏膜炎还没有有效的治疗方法，因此需要开发一种抗黏膜炎药物用于临床。本研究探讨了组蛋白去乙酰化酶抑制剂 Azatyrosine-PBHA（AzP）对肠黏膜是否具有治疗作用。结果表明，AzP 不会影响癌细胞的增殖和活力，而 suberoylanilide hydroxamic acid（SAHA）则可以达到这种效果。然而，AzP 可以减少炎症介质白细胞介素-6（IL-6）、单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）的产生。体内组织病理学评估表明，AzP 减轻了顺铂引起的空肠绒毛损伤，并导致 C57BL/6 小鼠体重减轻。免疫组织化学（IHC）结果表明，接受 AzP 治疗的小鼠也从顺铂引起的肠黏膜损伤中恢复。使用 DAVID/KEGG 富集分析微阵列数据和 Western blot 进行的体外机制研究表明，AzP 影响 MEK/ERK 和 AKT 依赖性途径。综上所述，本研究表明，AzP 可能通过调节 MEK/ERK MAPK 信号通路来减轻 MCP-1、TNF-α 和 IL-6 的产生，为开发针对黏膜炎的新型抗炎药物提供了机会。
