title: SNX-2112, a novel Hsp90 inhibitor, induces G2/M cell cycle arrest and apoptosis in MCF-7 cells.
abstract: SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.
authors.affiliation: Guangzhoujinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center for Genetic Medicine, Jinan University, West Huangpu Road, Guangzhou, China.
authors.forename: Shao-Xiang
authors.initials: SX
authors.lastname: Wang
authors.forename: Huai-Qiang
authors.initials: HQ
authors.lastname: Ju
authors.forename: Kai-Sheng
authors.initials: KS
authors.lastname: Liu
authors.forename: Jia-Xuan
authors.initials: JX
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Yang-Fei
authors.initials: YF
authors.lastname: Xiang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Jin-Yun
authors.initials: JY
authors.lastname: Liu
authors.forename: Qiu-Ying
authors.initials: QY
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Guo-Wen
authors.initials: GW
authors.lastname: Xing
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D053453:Caspase 9; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C534922:SNX 2112; C112765:tanespimycin