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Current Topics in Pharmacology   Volumes    Volume 14 
Pharmacological inhibition of Hsp90: Promising approaches to targeted therapy of cancer
Alexander E. Kabakov, Vladimir A. Kudryavtsev
Pages: 89 - 102
Number of pages: 14
Current Topics in Pharmacology
Volume 14 

Copyright © 2010 Research Trends. All rights reserved

In vivo, heat shock protein 90 (Hsp90) functions as an ATP-dependent chaperone catalyzing maturation and activation of client proteins. A number of its client proteins are implicated in cancer-associated pathways that ensure tumor growth and resistance to therapeutics; in the case of Hsp90 dysfunction, these proteins are destabilized and degraded thus impairing the proliferative/defensive potential of cancer cells. Consequently, suitable inhibitors of Hsp90 could be applied as effective anticancer agents. Two low-toxic analogues of Geldanamycin, 17-N-allilamino-17-demethoxygeldanamycin (17AAG) and 17-N-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG), are the Hsp90 inhibitors which exhibited prominent anticancer activity in many oncology-relevant models and primary clinical trials. It was found that clinically achievable concentrations of these drugs can kill or repress cells of human leukemia and some solid tumors. Moreover, 17AAG and 17DMAG are able to sensitize malignancies to other chemotherapeutic drugs, radiotherapy and immunotherapy. The most optimistic prospects are based on the fact that Hsp90 in cancer cells binds 17AAG with ~100-fold higher affinity than Hsp90 in normal cells. Such a difference suggests that in the patient’s organism the drug will preferentially target malignant cells and the drug-induced cytotoxicity will be localized within tumors. In addition, 17AAG and 17DMAG were shown to suppress the vascularization, invasiveness and metastasing of tumors. The present review generalizes numerous data on anticancer effects of the Hsp90 inhibitors and affords insight into molecular machinery of those effects. Potential trends and problems in the application of Hsp90 inhibitors to cancer treatment are also discussed.
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