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A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

Authors
 Sung-Kyun Ko  ;  Jiyeon Kim  ;  Deuk Chae Na  ;  Sookil Park  ;  Seong-Hyun Park  ;  Ji Young Hyun  ;  Kyung-Hwa Ba다  ;  Nam Doo Kim  ;  Nak-Kyoon Kim  ;  Young Nyun Park  ;  Kiwon Song  ;  Injae Shin 
Citation
 CHEMISTRY & BIOLOGY , Vol.22(3) : 391-403, 2015 
Journal Title
CHEMISTRY & BIOLOGY
ISSN
 1074-5521 
Issue Date
2015
MeSH
Adenosine Triphosphatases/antagonists & inhibitors* ; Adenosine Triphosphatases/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects* ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology* ; HSP70 Heat-Shock Proteins/antagonists & inhibitors* ; HSP70 Heat-Shock Proteins/drug effects ; HeLa Cells ; Hep G2 Cells ; Humans ; Imidazoles/pharmacology* ; Male ; Mice ; Mice, Nude ; Neoplasms/drug therapy* ; Neoplasms/enzymology ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Binding ; Random Allocation ; Xenograft Model Antitumor Assays
Abstract
The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.
Full Text
http://www.sciencedirect.com/science/article/pii/S1074552115000587
DOI
10.1016/j.chembiol.2015.02.004
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140658
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