The Molecular Aspect of Antitumor Effects of Protease Inhibitor Nafamostat Mesylate and Its Role in Potential Clinical Applications.

Xi Chen,Shuangshuang Zeng,Jie Wei,Xue Yang,Qiuying Shen,Yuanliang Yan,Zhijie Xu,Wanli Liu,Xiang Wang,Long Qian,Zhicheng Gong

doi:10.3389/fonc.2019.00852

Abstract

Nafamostat mesylate (NM), a synthetic serine protease inhibitor first placed on the market by Japan Tobacco in 1986, has been approved to treat inflammatory-related diseases, such as pancreatitis. Recently, an increasing number of studies have highlighted the promising effects of NM in inhibiting cancer progression. Alone or in combination treatments, studies have shown that NM attenuates various malignant tumors, including pancreatic, colorectal, gastric, gallbladder, and hepatocellular cancers. In this review, based on several activating pathways, including the canonical Nuclear factor-κB (NF-κB) signaling pathway, tumor necrosis factor receptor-1 (TNFR1) signaling pathway, and tumorigenesis-related tryptase secreted by mast cells, we summarize the anticancer properties of NM in existing studies both in vitro and in vivo. In addition, the efficacy and side effects of NM in cancer patients are summarized in detail. To further clarify NM's antitumor activities, clinical trials devoted to validating the clinical applications and underlying mechanisms are needed in the future.

Highlights

Cancer is a worldwide public health problem and has been the major cause of death in recent years [1]
In this review, based on several activating pathways, including the canonical Nuclear factor-κB (NF-κB) signaling pathway, tumor necrosis factor receptor-1 (TNFR1) signaling pathway, and tumorigenesis-related tryptase secreted by mast cells, we summarize the anticancer properties of Nafamostat mesylate (NM) in existing studies both in vitro and in vivo
The study of Homma et al was confirmed that NM influenced IFN-γ-induced human leukocyte antigen-ABC (HLA-ABC) up-regulation in lung cancer and pancreatic cancer [11], suggesting that NM may improve the treatment of immune resistant cancer

Summary

INTRODUCTION

Cancer is a worldwide public health problem and has been the major cause of death in recent years [1]. Another study confirmed that the combination of NM sensitized oxaliplatin-induced NF-κB/p65 activation via suppressing phosphorylated IκBα and IKKα/β in colorectal cancer, resulting in reduced cell proliferation, increased apoptosis in vitro and decreased tumor growth in vivo [15]. A number of studies indicate that both NF-κB and p53 are activated in response to DNA damage by ionizing radiation and modulate each other’s activities [37] Besides these classical strategies, some novel molecular inhibiters were confirmed to improve the antitumor effects of NM through pathways related to NF-κB signaling. Haruki et al found that addition of glycogen synthase kinase-3 (GSK-3) inhibitor to NM significantly decreased the NFκB/p65 activation and inhibited the cell proliferation in TABLE 1 | The anti-tumor activities of combination of NM and chemotherapy/radiotherapy in vitro. NOZ cells p65 and phosphorylated IκBα; Cleaved caspase-8/caspase-3; p65; cleaved caspase-8/caspase-3; Mdm2/p53/ p21Waf1/Cip ; p65, phosphorylated IκBα and phosphorylated IKKα/β; Cleaved caspase9/caspase-3/PARP; phosphorylated Erk; p65; Cleaved caspase-8/caspase3/caspase-9/PARP; MMP-2 and MMP-9; p65 and phosphorylated IκBα; Cleaved caspase-8/caspase-3/ PARP; p65, p50, and phosphorylated IκBα; Cleaved caspase8/caspase-3/ PARP; p65 and phosphorylated IκBα; Cleaved caspase8/PARP; Induction of apoptosis and G2/M arrest

DISCUSSION

Findings

A Brief Comparison Between NM and Other Protease Inhibitors

CONCLUSIONS