Inhibitors of the HSP90 Molecular Chaperone: Current Status

Sharp, Swee Y.; Workman, Paul

doi:10.1016/s0065-230x(06)95009-x

Cited by 294 publications

(272 citation statements)

References 94 publications

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“…However, cdc25c seems to be degraded by calpains. GA derivatives such as 17-AAG and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) are undergoing clinical trials of different kind of tumours, showing promising results (Drysdale et al, 2006;Sharp and Workman, 2006;Xiao et al, 2006). Based on our results, we can conclude that ansamycins may have a potential to be used in the clinic for the treatment of glioblastomas, either as single agents or in combination with other antitumour agents or radiotherapy.…”

Section: Discussionmentioning

confidence: 67%

Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G2/M arrest in glioblastoma cell lines

et al. 2007

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Ansamycins exert their effects by binding heat shock protein 90 (Hsp90) and targeting important signalling molecules for degradation via the proteasome pathway. We wanted to study the effect of geldanamycin (GA) and its derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) on glioblastoma cell lines. We show that these cells are growth inhibited by ansamycins by being arrested in G 2 / M and, subsequently, cells undergo apoptosis. The protein levels of cell division cycle 2 (cdc2) kinase and cell division cycle 25c (cdc25c) were downregulated upon GA and 17-AAG treatment and cdc2 kinase activity was inhibited. However, other proteins involved in the G 2 /M checkpoint were not affected. The cdc2 and cdc25c mRNA levels did not show significant differences upon ansamycin treatment, but the stability of cdc2 protein was reduced. The association of cdc2 and cdc25c with p50 cdc37 , an Hsp90 cochaperone, decreased, but the interaction of cdc2 and cdc25c with the Hsp70 co-chaperone increased after ansamycin treatment. Proteasome inhibitors were able to rescue the cdc2 downregulation, but not the cdc25c reduction. However, calpain inhibitors were able to rescue the cdc25c downregulation, suggesting that cdc25c is proteolysed by calpains in the presence of ansamycins, and not by the proteasome. We conclude that ansamycins downregulate cdc2 and cdc25c by two different mechanisms.

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Section: Discussionmentioning

confidence: 67%

Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G2/M arrest in glioblastoma cell lines

et al. 2007

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“…Scale bars correspond to 10 µm. 17-AAG is a geldanamycin analog that inhibits Hsp90 by displacing ATP from its ATP binding pocket and thereby functionally arrests the chaperone cycle of Hsp90 (Sharp and Workman, 2006;Whitesell and Lindquist, 2005). Hsp90 is a major cytosolic chaperone and has been shown to refold Fluc upon recovery from heat stress (Schneider et al, 1996).…”

Section: V34 Effect Of Fluc-egfp-based Sensors On the Cytosolic Stmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Several antitumor fungal antibiotics including geldanamycin have been shown to inhibit Hsp90-dependent unfolding of p53 (Blagosklonny et al, 1996). Compounds targeting Hsp90 are already undergoing clinical trials (reviewed by Sharp and Workman, 2006).…”

Section: Current Strategies For Mutant P53 Rescuementioning

confidence: 99%