title: A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities.
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.
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sung-Kyun
authors.initials: SK
authors.lastname: Ko
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Deuk Chae
authors.initials: DC
authors.lastname: Na
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sookil
authors.initials: S
authors.lastname: Park
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Seong-Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Hyun
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Kyung-Hwa
authors.initials: KH
authors.lastname: Baek
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 706-010, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Nak-Kyoon
authors.initials: NK
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Song
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea. Electronic address: injae@yonsei.ac.kr.
authors.forename: Injae
authors.initials: I
authors.lastname: Shin
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; C483693:Hspa14 protein, human; D007093:Imidazoles; D000251:Adenosine Triphosphatases