Document Detail


A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells.
MedLine Citation:
PMID:  20012863     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. METHODS: We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. RESULTS: VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. CONCLUSION: These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.
Authors:
Andrew J Massey; Douglas S Williamson; Helen Browne; James B Murray; Pawel Dokurno; Terry Shaw; Alba T Macias; Zoe Daniels; Stephanie Geoffroy; Melanie Dopson; Paul Lavan; Natalia Matassova; Geraint L Francis; Christopher J Graham; Rachel Parsons; Yikang Wang; Antony Padfield; Mike Comer; Martin J Drysdale; Mike Wood
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Publication Detail:
Type:  Journal Article     Date:  2009-12-13
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  66     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-07-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  535-45     Citation Subset:  IM    
Affiliation:
Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK. a.massey@vernalis.com
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects*
Breast Neoplasms / drug therapy,  pathology
Caspase 3 / metabolism
Caspase 7 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy,  pathology
Drug Delivery Systems
Drug Synergism
Female
HSC70 Heat-Shock Proteins / antagonists & inhibitors*
HSP70 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / antagonists & inhibitors*,  metabolism
Humans
Purine Nucleosides / pharmacokinetics,  pharmacology*
Chemical
Reg. No./Substance:
0/HSC70 Heat-Shock Proteins; 0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; 0/Purine Nucleosides; 0/VER 155008; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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