title: The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-κB and disruption of mitochondria-dependent pathways.
abstract: Heat shock protein 90 (Hsp90) serves as an ATP-dependent molecular chaperone for numerous cell signaling proteins, including many oncogenes and clinically validated cancer targets that are involved in cell proliferation and survival. Recent studies have shown that the Hsp90 inhibitor, SNX-2112, effectively inhibits tumor cell growth and angiogenesis in hematological and solid tumors. However, little is known about the effects of SNX-2112 on leukemias that are resistant to chemotherapy, which is emerging as a major clinical problem. In this study, the effects of SNX-2112 on the multidrug-resistant human chronic myeloid leukemia (CML) K562/ADR cell line were investigated. We observed that SNX-2112 exhibited dose- and time-dependent inhibitory activities against K562/ADR cells. These effects included the induction of apoptosis and secondary necrosis in addition to cell cycle arrest at the G1 and G2 phases. Furthermore, SNX-2112-induced apoptosis was predominantly mediated by the mitochondrial pathway, initiated by the release of cytochrome c and the participation of Bcl-2 family proteins. SNX-2112 also induced the activation of the caspase-3, -8 and -9 cascade and the subsequent cleavage of PARP in K562/ADR cells. Moreover, the inactivation of the Akt and NF-κB signaling pathways may be involved in SNX-2112-induced apoptosis. The expression levels of P-glycoprotein (P-gp) and several chaperons related to drug resistance and apoptosis were also shown to be inhibited, including the Grp78 and Hsp90 isoforms, Grp94 and Trap1. Taken together, these results provide a possible molecular mechanism for the anti-cancer effect of SNX-2112 on K562/ADR cells and provide new insights into the future application of SNX-2112 as a therapeutic agent for anti-multidrug-resistant leukemias.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Shao
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Chen
authors.forename: Kaisheng
authors.initials: K
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C534922:SNX 2112; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: 17-(allylamino)-17-demethoxygeldanmycin; 17-AAG; 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide; 4,6-diamidino-2-phenylindole; 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide; ANOVA; Apoptosis; BCA; CML; DAPI; DMSO; FBS; FITC; Hsp90; JC-1; Leukemia; MDR; MMP; MTT; Mitochondrial dysfunction; P-glycoprotein; P-gp; PBS; PI; PVDF; SNX-2112; TUNEL; bicinchoninic acid; chronic myeloid leukemia; dimethylsulfoxide; fetal bovine serum; fluorescein isothiocyanate; heat shock protein 90; mitochondrial transmembrane potential; multidrug resistance; one-way analysis of variance and covariance; phosphate-buffered saline; polyvinyl difluoride; propidium iodide; terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling