title: Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells.
abstract: Heat shock protein 90 (Hsp90) contains amino (N)-terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states.
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Yingting
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Fujian Institute of Hematology, Union Hospital, FMU, Fuzhou, China.
authors.forename: Xianling
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Deptartment of Biopharmaceutics, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Xiaole
authors.initials: X
authors.lastname: Chen
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Yingjuan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Fujian Institute of Hematology, Union Hospital, FMU, Fuzhou, China.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.|Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China.
authors.forename: Lixian
authors.initials: L
authors.lastname: Wu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D050939:Gene Fusion; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000072417:Protein Domains; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C581634:BCR-ABL1 fusion protein, human; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D016044:Fusion Proteins, bcr-abl; D002945:Cisplatin
keywords: Bcr-Abl; Hsp90; amino terminal; carboxyl terminal; imatinib-resistant