Biological Evaluation of Alkyl Triphenylphosphonium Ostruthin Derivatives as Potential Anti-Inflammatory Agents Targeting the Nuclear Factor κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

Nghia Trong Vo,Kaori Nakano,Chihiro Moriwaki,Sayuri Fukuhara,Phu Hoang Dang,Yasunobu Miyake,Eiichi Kusagawa,Sayaka Haruyama,Takao Kataoka,Nhan Trung Nguyen,Mai Thanh Thi Nguyen

doi:10.3390/biochem1020010

Abstract

Ostruthin (6-geranyl-7-hydroxycoumarin) is one of the constituents isolated from Paramignya trimera and has been classified as a simple coumarin. We recently reported the synthesis of alkyl triphenylphosphonium (TPP) derivatives from ostruthin and evaluated their anticancer activities. In the present study, we demonstrated that alkyl TPP ostruthin derivatives inhibited the up-regulation of cell-surface intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells stimulated with tumor necrosis factor-α (TNF-α) without affecting cell viability, while ostruthin itself exerted cytotoxicity against A549 cells. The heptyl TPP ostruthin derivative (termed OS8) attenuated the up-regulation of ICAM-1 mRNA expression at concentrations higher than 40 µM in TNF-α-stimulated A549 cells. OS8 inhibited TNF-α-induced nuclear factor κB (NF-κB)-responsive luciferase reporter activity at concentrations higher than 40 µM, but did not affect the translocation of the NF-κB subunit RelA in response to the TNF-α stimulation at concentrations up to 100 µM. A chromatin immunoprecipitation assay showed that OS8 at 100 µM prevented the binding of RelA to the ICAM-1 promoter. We also showed that OS8 at 100 µM inhibited the TNF-α-induced phosphorylation of RelA at Ser 536. Moreover, the TNF-α-induced phosphorylation of an inhibitor of NF-κB α and extracellular signal-regulated kinase was reduced by OS8. These results indicate that OS8 has potential as an anti-inflammatory agent that targets the NF-κB signaling pathway.

Highlights

Cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1; known as CD54), play an essential role in the recruitment of leukocytes in blood vessels and their migration to local inflammation sites [1,2]
We evaluated the anti-inflammatory activities of ostruthin and its TPP derivatives with different lengths of alkyl linkers in human lung adenocarcinoma A549 cells (Figure 1)
ICAM-1 mRNA expression in a dose-dependent manner and strongly at concentrations of 70 and 100 μM (Figure 4F). These results demonstrated that OS8 inhibited tumor necrosis factor-α (TNF-α)-induced ICAM-1 transcription

Summary

Introduction

Cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1; known as CD54), play an essential role in the recruitment of leukocytes in blood vessels and their migration to local inflammation sites [1,2]. The up-regulation of ICAM-1 on endothelial cells is stimulated by proinflammatory cytokines, such as tumor necrosis. We recently reported the synthesis and biological evaluation o phenylphosphonium (TPP) ostruthin derivatives to enhance the pharmacoki ties of ostruthin [17]. Ostruthin TPP derivatives with diff factor-α and interleukin-1. These proinflammatory cytokines primarily induce of alkyl(TNF-α) linkers were found [3]. To exert stronger or weaker cytotoxic activities ag the nuclear factor κB (NF-κB) signaling pathway [4,5].

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Conclusion