Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage

Lim, Ju Hee; Kim, Kyeong-Man; Kim, Seong Who; Hwang, Onyou; Choi, Hyun Jin

doi:10.1016/j.phrs.2008.03.004

Cited by 127 publications

(78 citation statements)

References 38 publications

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“…Because many studies have reported the contribution of PI3K/ Akt to the activation of Nrf2 signaling (Feng et al, 2011;Lim et al, 2008), we evaluated whether this pathway is involved in 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. Activation of this pathway is dependent on the phosphorylation status of both Thr308 and Ser473 residues (Alessi et al, 1996), and is known to facilitate both the release of Nrf2 from Keap1 and its subsequent translocation into the nucleus as well as AREpromoter activation (Papaiahgari et al, 2006).…”

Section: The Pi3k/akt Pathway Is Involved In 4-mc-induced Inhibition mentioning

confidence: 99%

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

Lim

Lee

Cho

et al. 2013

Molecules and Cells

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti-cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling.

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Section: The Pi3k/akt Pathway Is Involved In 4-mc-induced Inhibition mentioning

confidence: 99%

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

Lim

Lee

Cho

et al. 2013

Molecules and Cells

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“…Increased levels of phase II enzymes and their genes such as HO1 , NQO1 , SOD , GPx , and CAT have been associated with increased oxidative stress during aging in animal and human studies [38,39,40,41,42,43,44,45]. In Alzheimer disease, increased HO1 and NQO1 activity offers cytoprotection to neurons [42,43].…”

Section: Discussionmentioning

confidence: 99%

<b><i>Piper betle </i></b>Induced Cytoprotective Genes and Proteins via the Nrf2/ARE Pathway in Aging Mice

et al. 2016

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Background/Aims: The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins. Methods: Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis. Results: PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis-acting motif located in the promoter region of nearly all phase II genes. Conclusions: PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process.

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“…16,19,20) To identify the signaling pathway involved in HMC05-mediated NQO-1 induction, we assessed the effects of selective chemical inhibitors of signaling via MAPKs, PI3K, GGTase 1 and farnesyltransferase (FTase). Interestingly, the inhibitors of extracellular signal-regulated kinase (ERK) (PD98059), p38 MAPK (SB203580), JNK (JNK inhibitor II) and PI3K (LY294001 and wortmannin) had no effects on HMC05-mediated NQO-1 induction (Fig.…”

Section: The Reversal Of the Protective Effect Of Hmc05 Through The Imentioning

confidence: 99%

The Small GTPases Regulate HMC05-Induced NQO-1 Expression with an Antioxidant Effect in Smooth Muscle Cells

Gum

Shin

Cho

2014

Biological & Pharmaceutical Bulletin

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Recently, Banhabackchulchunmatang (HMC05) has been implicated as a preventive and/or therapeutic candidate for cardiovascular diseases due to its inhibition of atherosclerosis lesions and its reduction of neointima formation. Knowledge of the mechanism of HMC05 in smooth muscle cells (SMC) is limited. However, SMC may be a potential target for HMC05 therapy because they are supported by the HMC05-mediated preservation of medial smooth muscle cell layers in pathogenic progression. Therefore, in the present study, we hypothesized that the effect of HMC05 is associated with reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase-1 (NQO-1) gene regulation, which precipitates an antioxidant effect in SMC. HMC05 significantly increased NQO-1 gene expression in a dose-and time-dependent manner. The reactive oxygen species-mediated toxicity that was generated by xanthine/xanthine oxidase was suppressed by HMC05. The knockdown of the NQO-1 gene abrogated the HMC05-mediated cytoprotection. Key words HMC05; isoprenylation; smooth muscle cell; reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase-1 (NQO-1) HMC05 is a water extract of Banhabackchulchunmatang that has been used for headaches and hypertension in traditional herbal medicines.1) A pilot study on the reduction of blood pressure by HMC05 was performed in a randomized, single-blind cross over trial.2) Recently, HMC05 was demonstrated to lead to potent inhibition of atherosclerosis lesions in high-fat and high-cholesterol-fed apoE-knockout mice, which was partially attributed to anti-inflammatory effects.3) Neointimal formation was also reduced by HMC05 via the inhibition of PDGF-mediated cellular signaling in balloon-injured carotid arteries.1) Therefore, HMC05 is a candidate for anti-atherosclerosis agent that has also been used as an herbal medicine. HMC05 shows no toxicity in humans and is standardized based on berberine and hesperidin. Interestingly, the medial smooth muscle cell layer was preserved via the administration of HMC05 at both balloon injury sites and atherosclerotic lesions; this indicates that smooth muscle cells (SMC) may be a promising target of HMC05 for the prevention of cardiovascular diseases.Reactive oxygen species (ROS) play a critical role in pathophysiology of vascular disease.4) ROS production in atherosclerotic lesions accelerates the migration of SMC from the media to the intima, which leads to the development of a fibrous thickened layer. SMC are therefore promising in targeting vascular redox signaling to prevent ROS. Reduced nicotinamide adenine dinucleotide phosphate (NAD(P) H): quinone oxidoreductase-1 (NQO-1) (EC 1.6.99.2) is a homodimeric flavoprotein that catalyzes a two-electron reduction of electrophilic quinone substrates.5) Inducible NQO-1 expression plays a major role as a potential O 2 − · scavenger in SMC. 6)Several phytochemicals inhibiting oxidative stress have a beneficial effect in atherosclerosis and restenosis via their direct antioxidant actions. 7-9) Th...

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Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage

Cited by 127 publications

References 38 publications

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

<b><i>Piper betle </i></b>Induced Cytoprotective Genes and Proteins via the Nrf2/ARE Pathway in Aging Mice

The Small GTPases Regulate HMC05-Induced NQO-1 Expression with an Antioxidant Effect in Smooth Muscle Cells

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