A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma

Ronnen, Ellen A.; Kondagunta, G. Varuni; Ishill, Nicole; Sweeney, Suzanne M.; DeLuca, John; Schwartz, Lawrence H.; Bacik, Jennifer; Motzer, Robert J.

doi:10.1007/s10637-006-9208-z

Cited by 145 publications

(104 citation statements)

References 14 publications

(16 reference statements)

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“…We also have shown that HSP70i is localized at the centrosome in mitotic HeLa cells (Supplementary data). HSP90 inhibitors 17-AAG and 17-DMAG are now in clinical trials (Ramanathan et al, 2005;Shadad and Ramanathan, 2006;Nowakowski et al, 2006;Ronnen et al, 2006). A recent study identifies 17-AAG-induced kinetochore defects as a possible mechanism of HSP90 inhibitor-induced mitotic arrest (Niikura et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of α-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of α-tubulin in mitotic cells showed spindle formation in arsenite-and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. γ-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

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Section: Discussionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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“…Concerning polyQ diseases, these two compounds have been shown to have beneficial effects only for SBMA [19][20][21]. Despite its high potency, 17-AAG showed poor solubility and stability and demonstrated moderate toxicity in several clinical trials [22]. In contrast, 17-DMAG is a more potent analog of 17-AAG [23], is more water soluble than 17-AAG and can be administered orally [24], which could be advantageous for clinical purposes.…”

Section: Introductionmentioning

confidence: 99%

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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“…17-AAG is the first HSP90 inhibitor used clinically (5), but a clinical trial showed it not to be effective against renal cancer when administered alone (6). Ritonavir is an HIV protease inhibitor widely used for treating HIV infection and has recently been found to have antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

“…The geldanamycin derivative 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is the first HSP90 inhibitor to be used clinically (5). It seems to be a promising anticancer agent with a novel mechanism of action, but a phase II clinical trial investigating the efficacy of 17-AAG found it not to be effective against renal cancer (6).…”

Section: Introductionmentioning

confidence: 99%

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

2012

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Abstract. Our previous study showed that the combination of a histone deacetylase (HDAC) inhibitor and an HIV protease inhibitor is effective against renal cancer cells. Because HDAC inhibition disrupts the chaperon function of heat shock protein (HSP) 90, we hypothesized that the combination of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, and the HIV protease inhibitor ritonavir would also act against renal cancer. The combination of 17-AAG and ritonavir induced apoptosis and inhibited the proliferation of renal cancer cells effectively. It also suppressed the expression of cyclin-dependent kinase 4 and cyclin D1, leading to the accumulation of the cells in the sub-G1 fraction. The expression of HSPs 27, 70 and 90 was increased by 17-AAG alone but reduced by 17-AAG combined with ritonavir. The combination decreased the expression of heat shock factor-1 (HSF-1), an HSP transcription factor, and this might be one of the mechanisms of the effect of the combination. We have also found that silencing of HSF-1 by siRNA inhibited the proliferation of renal cancer cells and that in surgically resected specimens the levels of HSF-1 expression in renal cancer tissue are higher than those in normal parenchyma. This is the first study showing the beneficial effect of combining 17-AAG and ritonavir and our data suggest that HSF-1 may be a novel therapeutic target in the treatment of renal cancer. IntroductionAlthough recently introduced novel anticancer agents such as inhibitors of tyrosine kinase (1,2) and the mammalian target of rapamycin (3) are promising against advanced renal cancer, new treatment approaches are needed because curative agents are not yet available.Inhibition of heat shock protein 90 (HSP90) destabilizes the cancer cell's aberrant protein subset, leading to protein degradation by proteasomes (4). The geldanamycin derivative 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is the first HSP90 inhibitor to be used clinically (5). It seems to be a promising anticancer agent with a novel mechanism of action, but a phase II clinical trial investigating the efficacy of 17-AAG found it not to be effective against renal cancer (6).We have previously shown that the combination of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and the HIV protease inhibitor ritonavir is effective against renal cancer by inhibiting the HDAC function and expression, leading to extensive histone acetylation (7). SAHA inhibits HDAC6, and ablation of HDAC6 has been shown to induce hyperacetylation of HSP 90, disrupting its chaperone function (8,9). We therefore thought that combining ritonavir with 17-AAG would be more effective against renal cancer because 17-AAG could inhibit HSP90 function more directly than SAHA does.In the present study, we investigated the combined effect of 17-AAG and ritonavir against renal cancer by using renal cancer cell lines and found that the combination inhibited the renal cancer growth by inhibiting the expression of heat shock factor-1 (HSF-1), an HS...

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A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma

Cited by 145 publications

References 14 publications

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

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

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

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