In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative

Hollingshead, Melinda G.; Alley, Michael C.; Burger, Angelika M.; Borgel, Suzanne; Pacula-Cox, Christine; Fiebig, Heinz‐Herbert; Sausville, Edward A.

doi:10.1007/s00280-004-0939-2

Cited by 146 publications

(106 citation statements)

References 21 publications

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“…Previous studies have shown increased oral availability of 17-DMAG in comparison with 17-AAG; however, above 10 mg/kg 17-DMAG has been described to be toxic in mice [33]. It has also been demonstrated that i.p.…”

Section: -Dmag Chronic Treatment Improved Several Features Of the Mmentioning

confidence: 92%

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

et al. 2014

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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein.Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.

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Section: -Dmag Chronic Treatment Improved Several Features Of the Mmentioning

confidence: 92%

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

et al. 2014

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“…16,18,53,54 Dosages were selected based on studies showing effective treatment and minimal toxicity at dosages under 15 mg/kg administered 3 days per week for 3 weeks. 55 We injected MRL/lpr mice with 17-DMAG 3 days a week on alternating days for 6 weeks, (a) Linear regression of grouped proteinuria scores showed control mice exhibited increased proteinuria, while mice treated with 17-DMAG did not increase in proteinuria. Linear regression for proteinuria in the control group was statistically significant with a P value less than 0.01.…”

Section: Hsp90 Inhibition Reduced Inflammatory Mediator Production Inmentioning

confidence: 99%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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“…Included among these are 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG, KOS1022; alvespimycin; compound 35, Figure 5; Tian et al, 2004;Hollingshead et al, 2005) and JPI-504 (compound 36, Figure 5; Ge et al, 2008), each having entered clinical trials.…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative

Abstract: Taken together, the in vivo activity of 17-DMAG supports the further development of this water-soluble and potentially orally administrable geldanamycin congener.

Cited by 146 publications

References 21 publications

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

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