1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling.

Lars-Oliver Klotz,Xiaoqing Hou,Claus Jacob

doi:10.3390/molecules190914902

Abstract

Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others) to cellular and inter-cellular signaling processes are discussed: (i) naphthoquinone-induced Nrf2-dependent modulation of gene expression and its potentially beneficial outcome; (ii) the modulation of receptor tyrosine kinases, such as the epidermal growth factor receptor by naphthoquinones, resulting in altered gap junctional intercellular communication. Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings.

Highlights

Naphthoquinones as Redox Cyclers and Alkylating AgentsVitamin K assists in coagulation by allowing for the γ-carboxylation of glutamyl residues of proteins involved in the blood clotting cascade—thereby generating calcium chelating moieties
Apart from the obvious use of K vitamers to antagonize vitamin K deficiencies, simple naphthoquinones as described in this article are mostly “potentials”—i.e., they are being investigated with respect to their use in cancer chemotherapy and numerous other therapeutic applications
One approach successfully tested in cell culture and in mice was the overexpression of manganese superoxide dismutase to catalyze the dismutation of superoxide to hydrogen peroxide—combined with an impairment of peroxide removal, e.g., through drugs interfering with glutathione metabolism [63,64]

Summary

Introduction

Vitamin K assists in coagulation by allowing for the γ-carboxylation of glutamyl residues of proteins involved in the blood clotting cascade—thereby generating calcium chelating moieties. Contributing to xenobiotic metabolism in that hydroquinones can undergo Phase II metabolism [7] (coupling of the hydroxyl moieties to water-soluble molecules to facilitate elimination), they may be unstable and be oxidized by oxygen to form the semiquinone and superoxide [7] This two-faced role of NQO1 in quinone metabolism was recently illustrated in HEK293 cells exposed to menadione [8]. Alkylation and redox cycling may join forces: after addition of glutathione to naphthoquinones—e.g., to C-3 in menadione, to result in 3-glutathionyl-2-methyl-1,4-naphthodiol [13]—the reaction product may undergo autoxidation, generating superoxide and the semiquinone and quinone forms, the latter of which may be reduced back by NQO1 [13]. See Reference [14] for a recent review

Naphthoquinone-Induced Intra- and Intercellular Signaling

Protein Tyrosine Phosphatases as Targets in Naphthoquinone-Induced Signaling

Conclusions

Naphthoquinones and Cancer Cells: “Death by ROS”

Naphthoquinones and PTPase Inhibition

Naphthoquinones and EGFR Activation—Alleviation of Side Effects?