Phytochemical Induction of Cell Cycle Arrest by Glutathione Oxidation and Reversal by N-Acetylcysteine in Human Colon Carcinoma Cells

Odom, Rosaline; Dansby, Montreka; Rollins-Hairston, Aisha; Jackson, Kimberly M.; Kirlin, Ward G.

doi:10.1080/01635580802549982

Cited by 23 publications

(14 citation statements)

References 24 publications

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“…Like other studies, we observed that the anti-proliferative action of DMF was linked to its ability to reduce intracellular GSH level [13,15,16]. The reduction of intracellular GSH increased the expression of HO-1 by human lung fibroblasts [34], and the depletion of GSH in airway epithelial cells ASMC up-regulated HO-1 expression [35,36].…”

Section: Resultssupporting

confidence: 60%

DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

et al. 2010

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BackgroundAirway wall remodelling is an important pathology of asthma. Growth factor induced airway smooth muscle cell (ASMC) proliferation is thought to be the major cause of airway wall thickening in asthma. Earlier we reported that Dimethylfumarate (DMF) inhibits platelet-derived growth factor (PDGF)-BB induced mitogen and stress activated kinase (MSK)-1 and CREB activity as well as IL-6 secretion by ASMC. In addition, DMF altered intracellular glutathione levels and thereby reduced proliferation of other cell types.MethodsWe investigated the effect of DMF on PDGF-BB induced ASMC proliferation, on mitogen activated protein kinase (MAPK) activation; and on heme oxygenase (HO)-1 expression. ASMC were pre-incubated for 1 hour with DMF and/or glutathione ethylester (GSH-OEt), SB203580, hemin, cobalt-protoporphyrin (CoPP), or siRNA specific to HO-1 before stimulation with PDGF-BB (10 ng/ml).ResultsPDGF-BB induced ASMC proliferation was inhibited in a dose-dependant manner by DMF. PDGF-BB induced the phosphorylation of ERK1/2 and p38 MAPK, but not of JNK. DMF enhanced the PDGF-BB induced phosphorylation of p38 MAPK and there by up-regulated the expression of HO-1. HO-1 induction inhibited the proliferative effect of PDGF-BB. HO-1 expression was reversed by GSH-OEt, or p38 MAPK inhibition, or HO-1 siRNA, which all reversed the anti-proliferative effect of DMF.ConclusionOur data indicate that DMF inhibits ASMC proliferation by reducing the intracellular GSH level with subsequent activation of p38 MAPK and induction of HO-1. Thus, DMF might reduce ASMC and airway remodelling processes in asthma.

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Section: Resultssupporting

confidence: 60%

DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

et al. 2010

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“…In both publications, the induction of p21 seems to be an important mechanism of regulation, as shown in our study. Interestingly, DMF can also induce G2/M cell cycle arrest, as shown in colon carcinoma cells and melanoma . Therefore, cell cycle inhibition by DMF seems to be a highly cell type‐specific method of regulation.…”

Section: Discussionmentioning

confidence: 99%

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Valesky

Hrgović

Doll

et al. 2016

Experimental Dermatology

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Different pathologies, such as lymphoedema, cancer or psoriasis, are associated with abnormal lymphatic vessel formation. Therefore, influencing lymphangiogenesis is an interesting target. Recent evidence suggests that dimethylfumarate (DMF), an antipsoriatic agent, might have antitumorigenic and antilymphangiogenic properties. To prove this assumption, we performed proliferation and functional assays with primary human dermal lymphendothelial cells (DLEC). We could demonstrated that DMF suppresses DLEC proliferation and formation of capillary-like structures. Underlying apoptotic mechanisms could be ruled out. Cell cycle analysis demonstrated a pronounced G1-arrest. Further evaluations revealed increases in p21 expression. In addition, DMF suppressed Cyclin D1 and Cyclin A expression in a concentration-dependent manner. p21 knockdown experiments demonstrated a p21-dependent mechanism of regulation. Further analysis showed an increased p21 mRNA expression after DMF treatment. This transcriptional regulation was enforced by post-transcriptional and post-translational mechanisms. In addition, we could demonstrate that the combination of a proteasomal inhibitor and DMF superinduced the p21 expression. Hence, DMF is a new antilymphangiogenic compound and might be used in various illnesses associated with increased lymphangiogenesis.

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“…Different authors have provided the first evidence that DMF treatment in vitro leads to growth inhibition of colon cancer of human and animal origin [5,6,16]. Furthermore, in vivo experiments with mouse models also suggest a colon cancer protective effect [8,17].…”

Section: Discussionmentioning

confidence: 99%

Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy

Kaluzki

Hailemariam-Jahn

Doll

et al. 2019

Cells

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Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct antitumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.

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Phytochemical Induction of Cell Cycle Arrest by Glutathione Oxidation and Reversal by N-Acetylcysteine in Human Colon Carcinoma Cells

Cited by 23 publications

References 24 publications

DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy

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