In Vitro Metabolism of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin in Human Liver Microsomes

Zheng, Nan; Zou, Peng; Wang, Shaomeng; Sun, Duxin

doi:10.1124/dmd.110.036418

Cited by 10 publications

(9 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17-DMAG primarily inhibits HSP90 by binding to the ATP binding site in the N-terminal domain of HSP9016, but due to benzoquinone reduction and GSH conjugation in its metabolism30, it also causes ROS production. Moreover, heat shock also induces ROS generation and DSBs directly, though the underlying mechanism has not been fully understood31.…”

Section: Discussionmentioning

confidence: 99%

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Huang

Zhou

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Due to the lack of effective treatment, hepatocellular carcinoma (HCC) is one of the malignancies with low survival rates worldwide. Combination of hyperthermia and chemotherapy has shown promising results in several abdominal tumours, but high expression of HSP90 in tumours attenuated the efficacy of hyperthermia. Thus a combination of hyperthermia and inhibition of HSP90 might be a feasible therapeutic strategy for HCC. One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). HCC cells of the combination group exhibited more G2/M arrest and higher apoptotic rates which might result from suffering from more reactive oxygen species and serious DNA damage. Heat shock/17-DMAG co-treatment of HCC cells also destabilized CDK1, Cyclin B1 and CDC25C with a concomitant decreased proportion of cells in the M phase. Furthermore, co-treatment impaired the interaction of HSP90α with CDC37 and with CDK1, accompanied with decreased soluble CDK1. Combination of 17-DMAG with a 1.5-h whole body hyperthermia treatment attenuated tumour growth in xenograft mice models. These results suggest hyperthermia sensitize HCC to 17-DMAG, and combination of hyperthermia with 17-DMAG might be a potential therapeutic strategy for HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Huang

Zhou

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This may explain the unchanged levels of CYP2E1 in 17-DMAG treated alcoholic livers. Further, 17-DMAG does not utilize GSH for metabolism in the liver likely retaining higher levels of free GSH [27] contributing to decreased alcohol mediated alleviating alcohol mediated oxidative stress in liver. Alcohol mediated oxidative stress at least in part, sensitizes liver macrophages to endotoxin resulting in elevation of pro-inflammatory cytokines and liver injury [19, 28].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

Ambade

Catalano

Lim

et al. 2014

Journal of Hepatology

View full text Add to dashboard Cite

Background & Aims Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG [17-Dimethylamino-ethylamino-17-demethoxygeldanamycin] in an in vivo mouse model of acute and chronic alcoholic liver injury. Methods C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analyzed. Results Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevents but also alleviates alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis shows that 17-DMAG decreases alcohol mediated oxidative stress, reduces serum endotoxin, decreases inflammatory cells, and diminishes sensitization of liver macrophages to LPS, resulting in down-regulation of CD14, NFκB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreases fatty acid synthesis genes via reduced nuclear SREBP-1 and favors fatty acid oxidation genes via PPARα. Conclusion Inhibition of hsp90 decreases alcohol induced steatosis and pro-inflammatory cytokines and inhibits alcoholic liver injury. Hsp90 is relevant in human alcoholic cirrhosis and promising therapeutic target in ALD.

show abstract

“…Since many Hsp90 clients are important for disease development, 17-DMAG is extensively studied for possible treatments of various diseases [21-25]. In this study, we have determined the effects of 17-DMAG and TNF treatments on multiple cell lines.…”

Section: Discussionmentioning

confidence: 99%

Combined effects of 17-DMAG and TNF on cells through a mechanism related to the NF-kappaB pathway

Dong

et al. 2013

Diagn Pathol

View full text Add to dashboard Cite

ObjectiveThe tumor necrosis factor (TNF) and the cellular NF-κB pathway protein IKKβ play important roles in various cellular processes such as cell proliferation, survival, differentiation, and apoptosis. A heat shock protein 90 inhibitor, 17-DMAG, can induce apoptosis of some tumor cells. This study is to determine the combined effects of 17-DMAG and TNF on malignant cells and the related mechanisms.MethodsWe have determined effects of 17-DMAG, an Hsp90 inhibitor, and TNF treatments on the small cell lung cancer cell line (MS-1), the adenocarcinoma cell line (A549), the squamous-cell carcinoma cell line (LK-2), and the normal human bronchial epithelium cell line (NuLi-1) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrozolium bromide assay. To determine if 17-DMAG inhibit the expression of IKKβ in the normal human NuLi-1 cells, and the malignant MS-1, A549, and LK-2 cells, immunoblotting assays and luciferase assays were performed.ResultsIt was found that the combined treatments resulted in synergistic killing of malignant cells, which was confirmed by the apoptosis determination using a fluorescence microscopic assay following staining of the drug-treated cells with Hoescht 33258. The immunoblotting results indicated that the synergistic killing due to 17-DMAG and TNF treatments may be related to the decreases in IKKβ levels in the presence of 17-DMAG.ConclusionsThe results suggest that combination of 17-DMAG and TNF treatments might be useful for treating malignancies upon further study in the further.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2041198513886824

show abstract

In Vitro Metabolism of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin in Human Liver Microsomes

Cited by 10 publications

References 26 publications

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

Combined effects of 17-DMAG and TNF on cells through a mechanism related to the NF-kappaB pathway

Contact Info

Product

Resources

About