A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling.

Hideaki Abe,Hiroshi Sakagami,Takanori Kamiya,Miwa Okazawa,Takahiro Oyama,Koichi Takao,Hiroaki Yamazaki,Takehiko Abe,Atsushi Yoshimori,Mitsutoshi Tsukimoto,Sei-Ichi Tanuma,Yoshiaki Sugita

doi:10.3390/medicines8040017

Abstract

Background: High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Methods: Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4′ position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.

Highlights

The results indicated that the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) by interaction with the extracellular tail of receptor for advanced glycation endoproducts (RAGE) was considerably inhibited by compound 3, resulting in a marked decrease in the production of inflammatory cytokines, such as IL-6 (Figure 3a)
The High mobility group box 1 (HMGB1)-RAGE axis serves as a key player in linking inflammation and carcinogenesis
The RAGE-RAGE ligand signaling pathway has been shown to drive the establishment of tumor microenvironment (TME) and is an important target for cancer therapeutics currently under development [29,30,39,63,64]

Summary

Introduction

T cells, and myeloid-derived suppressor cells (MDSCs), join in a tumor and generate an inflammatory tumor microenvironment (TME) that impairs anti-cancer immunity and. The establishment of the TME depends on the activation of certain transcription factors, including nuclear factor-κB (NFκB) and hypoxia-inducible factor-1α (HIF-1α), in cancer cells [13,14,15,16,17,18]. These transcription factors up-regulate the expression of inflammatory cytokines, such as interleukin-6 (IL-6)

Methods

Results

Discussion

Conclusion