Inhibition of Melanoma B16-F10 Growth by Lipid Peroxidation Product 4-Hydroxynonenal

Abstract

Since a gradual benign-to-malignant progression of murine melanoma B16 after exposure in vitro to hypoxia was described recently, the aim of this study was to test if exposing melanoma B16-F10 cells to aldehyde 4-hydroxynonenal (HNE), which is considered not only as one of the major "second toxic messengers" of oxygen free radicals (or oxidative stress), but as a normal constituent of many cells and tissues, might have opposite effects. Treatment of the tumor cells with 50 microM HNE in vitro or in vivo did not prevent development of the tumors, but inhibited their growth. Tumor growth inhibition was equal for in vitro and in vivo treatment, but appeared after a delay of almost one week, since there was no difference of the tumor volume to the control observed during the initial period of the tumor growth. Similarly, both HNE treatment of the tumor cells before transplantation and HNE treatment of the melanoma bearing mice resulted in equally prolonged survival time. Thus, the results obtained suggest that while hypoxia could increase the malignancy of the murine melanoma cells, exposing these cells to one of the major "second toxic messengers" of oxygen free radicals, HNE, has almost opposite effects and further indicate the possible use of the aldehyde in vivo.

Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling

“…ROS initiate an autocatalytic chain of lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs), resulting in the formation of large amounts of toxic electrophilic species and free radicals that may play important roles in various human diseases, including carcinogenesis (Poli et al, 2008; Esterbauer et al, 1991; Dianzani 2003; Zarkovic et al, 1995; Feng et al, 2004). In previous studies even a small transient exposure of cells to stress agents, such as UV, H 2 O 2 , or oxidant chemicals, causes substantial LPO, leading to a significant rise in 4HNE, which is considered to be one of the most abundant cytotoxic aldehydes (Yang et al, 2001; 2003b; Cheng et al, 2001a–c; Zarkovic et al, 1993).…”

“…The metabolism of 4HNE is mainly, although not entirely, conjugative, and proceeds via Michael addition of GSH to the double bond of 4HNE. This reaction is catalyzed by specialized GSTs (Awasthi et al, 2005a; 2008a; Esterbauer et al, 1991; Dianzani, 2003; Zarkovic et al, 1995; Ruef et al, 1998; Srivastava et al, 1998; Uchida et al, 1994). The intracellular concentration of 4HNE appears to be crucial for the nature of cell cycle signaling and may be a determinant for the signaling for differentiation, proliferation, transformation, or apoptosis.…”

“…4HNE is accumulated in numerous oxidative stress-related diseases, such as cardiovascular diseases and metabolic syndrome (Shoeb et al, 2014). 4HNE is also believed to be involved in the mechanisms of diseases such as atherosclerosis (Uchida et al, 1994; Yang et al, 2004), diabetes (Awasthi et al, 2010), Alzheimer’s disease (Sayre et al, 1997; Montine et al, 1997), Parkinson’s disease (Selley 1998), cataract (Awasthi et al, 1996), and cancer (Zarkovic et al, 1995; Hammer et al, 1997). …”

Evaluation of Immunostaining for 4-Hydroxy-2-Nonenal Receptors in Cutaneous Malignant Melanoma Immunohistochemical Study of 55 Cases

“…The obtained results suggest that while hypoxia can increase malignancy of murine MM cells, exposing these cells to one of the major "second toxic messengers" of oxygen free radicals, 4-HNE, has almost opposite effects and also suggests the possible use of this aldehyde in vivo [33].…”

Impaired Proliferation and DNA Synthesis of a Human Tumor Cell Line (HELA) Caused by Short Treatment with the Antianemic Drug Jectofer (Ferric-Sorbitol-Citrate) and the Lipid Peroxidation Product 4-Hydroxynonenal

“…19 The mechanism of cell growth modification caused by HNE involves interference with the expression of cellular proto-oncogenes.20,21 Those biological effects of HNE could hardly be considered as a consequence of the cytotoxicity of the aldehyde, particularly since cell growth modification was achieved even in the presence of the low, physiological concentrations of HNE.12-22-23 Furthermore, growth modifying effects of HNE depend on the presence of certain, not yet identified serum growth factors. [12][13][14][15][16][17][18][19][20][21][22] Due to the low concentrations of the aldehyde used and its high affinity to bind to proteins, it could even be possible that the observed effects of the HNE treatment were not the results of the activity of the aldehyde itself, but of the serum factors modified by HNE. If so, these serum factors are probably related to the growth factors which influence expression of the cellular proto-oncogenes and/or to factors involved in the mechanisms of oxidative stress.…”