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

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.

Figure 1

Structures of naphthoquinones. (A) Menadione (2-methyl-1,4-naphthoquinone), its α,β-unsaturated carbonyl moiety (gray) and the site of attack of a nucleophile in a Michael-type addition (red arrow); (B) Naphthoquinones mentioned in this article (see Table 1 for R2, R3, R5).

Figure 2

Loss of gap junctional intercellular communication (GJIC) in cells exposed to naphthoquinones. WB-F344 rat liver epithelial cells (a generous gift by Dr. James E. Trosko, Michigan State University, East Lansing, MI, USA) were grown to near confluence, followed by exposure to 10 µM of the given naphthoquinones (or DMSO as vehicle control) in serum-free cell culture medium (DMEM) for 60 min. Cells were washed with PBS and GJIC was determined by microinjecting the fluorescent dye Lucifer Yellow CH into selected cells as described previously [55,56]. One minute after injection, fluorescent cells surrounding the cells loaded with dye were counted and taken as a measure of GJIC. (A) Representative fluorescent and phase contrast images taken after microinjection of LY into the cell indicated by a yellow arrow; (B) 3 to 10 individual cells were loaded with dye per dish and means of the numbers of fluorescent neighboring cells were calculated. Data are means of three independent experiments performed in duplicate ± S.D. (lapachol, lawsone: n = 2, ±min/max).

Figure 3

Alkylation and redox cycling as initiators of naphthoquinone-induced signaling. Naphthoquinones (NQ), via oxidation or alkylation of cellular target structures, cause damage that may result in cell death. Stimulation of signaling cascades is triggered already at lower concentrations of NQ (with less extensive damage elicited). The figure provides examples of primary NQ target structures mentioned in the text, signaling cascades stimulated and biological effects elicited. PTPase—protein tyrosine phosphatase; RTK—receptor tyrosine kinase; GJIC—gap junctional intercellular communication.

Figure 4

Potential mechanisms for naphthoquinones to cause covalent modification of target proteins. The cysteine thiolate shown can be oxidized by ROS generated through redox cycling to form the corresponding cysteine sulfenate, sulfinate, or sulfonate, and ultimately also a disulfide.

Figure 5

Selenium- and tellurium-containing menadione-derivatives developed by the group of Claus Jacob as multifunctional redox catalysts [65].