Relationships between cell density, glutathione and proliferation of A549 human lung adenocarcinoma cells treated with acrolein

Horton, Noel D.; Mamiya, Blain M.; Kehrer, James P.

doi:10.1016/s0300-483x(97)00086-3

Cited by 61 publications

(31 citation statements)

References 30 publications

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“…This indicates that GSH depletion is an earlier event than cytotoxicity, evaluated by loss of cellular proliferation. There was also a correlation between acrolein-induced changes in GSH levels and inhibition of cell proliferation in A549 lung carcinoma cells (Horton et al, 1997). This is the first study that links GSH to induction of apoptosis by acrolein because pretreatment with NAC, a GSH precursor, inhibited acrolein-induced apoptosis.…”

Section: N-acetylcysteine Protects Against Acrolein-induced Apoptosis 79mentioning

confidence: 61%

Inhibition of Acrolein-Induced Apoptosis by the AntioxidantN-Acetylcysteine

Tanel¹,

Averill‐Bates²

2007

J Pharmacol Exp Ther

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Acrolein is a highly electrophilic ␣,␤-unsaturated aldehyde to which humans are exposed in many situations. It is an environmental pollutant that is responsible for multiple respiratory diseases and has been implicated in neurodegenerative diseases such as Alzheimer's disease. The hypothesis of the study is that the antioxidant N-acetylcysteine (NAC), a precursor of glutathione, could protect cells against acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to a noncytotoxic dose of acrolein (4 fmol/cell) depleted intracellular glutathione to 45% of initial levels. NAC, which increased intracellular glutathione levels by 30%, afforded protection against acroleininduced cytotoxicity (loss of cell proliferation) and apoptosis. NAC protected against apoptosis by diminishing acroleininduced activation of the mitochondrial death pathway. NAC inhibited acrolein-induced Bad translocation from the cytosol to the mitochondria, as well as Bcl-2 translocation from mitochondria to the cytosol, as evaluated by Western blot analysis. However, NAC had no effect on acrolein-induced Bax translocation to mitochondria and cytochrome c liberation into the cytosol. Meanwhile, NAC inhibited depolarization of mitochondrial membrane potential, as evaluated by rhodamine fluorescence using flow cytometry. NAC also inhibited procaspase-9 processing, activation of enzymatic activity of caspase-9, -7, and -8, and poly(ADP-ribose) polymerase cleavage induced by acrolein. Inhibition of acrolein-induced apoptosis using NAC was confirmed morphologically by diminished condensation of nuclear chromatin, as evaluated by fluorescence microscopy. These findings suggest that NAC could be potentially useful as a protective agent for people exposed to acrolein.

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Section: N-acetylcysteine Protects Against Acrolein-induced Apoptosis 79mentioning

confidence: 61%

Inhibition of Acrolein-Induced Apoptosis by the AntioxidantN-Acetylcysteine

Tanel¹,

Averill‐Bates²

2007

J Pharmacol Exp Ther

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“…The concentration of HNE required to induce apoptosis was severalfold higher than the IC 50 for the survival and growth assay, most likely because of a difference in the exposure conditions. The cells were at a higher density for the apoptosis experiments, a variable that is known to affect the absolute toxicity of ␣,␤-unsaturated aldehydes (Esterbauer et al, 1991;Norton et al, 1997). Another factor is that the cells were already attached in a monolayer for the apoptosis assay, with less surface area available and the potentially protective advantage of cell-cell interactions, whereas the exposure for the cytotoxicity assay was in suspension.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships for Growth Inhibition and Induction of Apoptosis by 4-Hydroxy-2-nonenal in Raw 264.7 Cells

et al. 2000

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4-Hydroxy-2-nonenal (HNE) is a highly reactive lipid aldehyde byproduct of the peroxidation of cellular membranes. The structure of HNE features three functional groups, a C1 aldehyde, a C2AC3 double bond, and a C4-hydroxyl group, each of which may contribute to the toxicity of the compound. In addition, the length of the aliphatic chain may influence toxic potency by altering lipophilicity. Using analogous compounds that lacked one or more of the structural moieties, the role of each of these structural motifs in the cytotoxicity of HNE was examined in a mouse alveolar macrophage cell line (RAW 264.7) by a cell survival and growth assay. The importance of these functional groups in the potency of HNE for induction of apoptosis was also examined. The rank order of effects on toxicity was C1Oaldehyde Ն C2AC3 double bond Ͼ Ͼ C4Ohydroxyl, with parallel results in both the survival/growth inhibition and apoptosis induction assays. The chain length also influenced toxicity in a series of ␣,␤-unsaturated alkenyl aldehydes, with increasing chain length yielding increasing toxicity. To confirm the importance of the aldehyde moiety, and to examine the role of metabolic detoxification in cellular defenses against HNE toxicity, a RAW 264.7 cell line overexpressing human aldehyde dehydrogenase-3 (hALDH3) was generated. This cell line exhibited nearly complete protection against HNEprotein adduct formation as well as HNE-induced apoptosis. These results illustrate the comparative significance of key structural features of HNE in relation to its potent toxicity and induction of apoptosis.

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“…Consequently, NF-B is released and translocates into the nucleus to activate NF-B dependent genes (22,24). The precise mechanisms by which acrolein regulates transcription are still poorly understood, but effects on glutathione, thioredoxin, IB kinase, mitogen-activated protein kinase, and Jun kinase have been reported (25)(26)(27)(28)(29)(30)(31)(32)(33). We report here that acrolein inhibits cytokine gene expression in human T lymphocytes primarily by alkylating cysteine and arginine residues on the p50 subunit.…”

mentioning

confidence: 86%

Acrolein Inhibits Cytokine Gene Expression by Alkylating Cysteine and Arginine Residues in the NF-κB1 DNA Binding Domain

Lambert¹,

Li²,

Jonscher

et al. 2007

Journal of Biological Chemistry

107

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Cigarette smoke is a potent inhibitor of pulmonary T cell responses, resulting in decreased immune surveillance and an increased incidence of respiratory tract infections. The ␣,␤-unsaturated aldehydes in cigarette smoke (acrolein and crotonaldehyde) inhibited production of interleukin-2 (IL-2), IL-10, granulocyte-macrophage colony-stimulating factor, interferon-␥, and tumor necrosis factor-␣ by human T cells but did not inhibit production of IL-8. The saturated aldehydes (acetaldehyde, propionaldehyde, and butyraldehyde) in cigarette smoke were inactive. Acrolein inhibited induction of NF-B DNA binding activity after mitogenic stimulation of T cells but had no effect on induction of NFAT or AP-1. Acrolein inhibited NF-B1 (p50) binding to the IL-2 promoter in a chromatin immunoprecipitation assay by >99%. Using purified recombinant p50 in an electrophoretic mobility shift assay, we demonstrated that acrolein was 2000-fold more potent than crotonaldehyde in blocking DNA binding to an NF-B consensus sequence. Matrix-assisted laser desorption/ionization time-offlight and tandem mass spectrometry demonstrated that acrolein alkylated two amino acids (Cys-61 and Arg-307) in the DNA binding domain. Crotonaldehyde reacted with Cys-61, but not Arg-307, whereas the saturated aldehydes in cigarette smoke did not react with p50. These experiments demonstrate that aldehydes in cigarette smoke can regulate gene expression by direct modification of a transcription factor.Cigarette smoke produces profound suppression of pulmonary immunity, resulting in an increased incidence and severity of respiratory tract infections. A recent Institute of Medicine study concluded that smoking increased the incidence of influenza and bacterial pneumonia and accounted for 19,000 smoking-related deaths per year (1). Children infected with Mycobacterium tuberculosis are five times more likely to develop pulmonary tuberculosis if exposed to cigarette smoke (2), and smoking doubles the risk of developing Pneumocystis carinii pneumonia in human immunodeficiency virus-infected individuals (3). Several studies have demonstrated that smoking suppresses T and B cell responses in the lungs without affecting cells in the peripheral blood (4 -7), but little research has been done to elucidate the underlying mechanism behind this phenomenon.We have recently identified two classes of immunosuppressive compounds in cigarette smoke. The dihydroxyphenols (hydroquinone and catechol) in the particulate phase inhibit T cell proliferation by blocking cell cycle progression in late G 1 and S phase (8 -12). In addition, the ␣,␤-unsaturated aldehydes, acrolein (CH 2 ACHCHO) and crotonaldehyde (CH 3 CHACHCHO) in the gas phase of cigarette smoke inhibit the production of several proinflammatory cytokines including IL-2, 4 tumor necrosis factor-␣, and granulocyte-macrophage colony-stimulating factor, with an IC 50 of 3 and 6 M, respectively (13). The saturated aldehydes (acetaldehyde, propionaldehyde, and butyraldehyde) have IC 50 values of Ͼ1500 M. The typical cigarett...

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Relationships between cell density, glutathione and proliferation of A549 human lung adenocarcinoma cells treated with acrolein

Cited by 61 publications

References 30 publications

Inhibition of Acrolein-Induced Apoptosis by the AntioxidantN-Acetylcysteine

Inhibition of Acrolein-Induced Apoptosis by the AntioxidantN-Acetylcysteine

Structure-Activity Relationships for Growth Inhibition and Induction of Apoptosis by 4-Hydroxy-2-nonenal in Raw 264.7 Cells

Acrolein Inhibits Cytokine Gene Expression by Alkylating Cysteine and Arginine Residues in the NF-κB1 DNA Binding Domain

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