title: Pan-BH3 mimetic S1 exhibits broad-spectrum antitumour effects by cooperation between Bax and Bak.
abstract: Small molecule S1 is a pan-BH3 mimetic that can bind antiapoptotic Bcl-2, Bcl-xL and Mcl-1 proteins. Herein, different Bcl-2 member expression cancer cell lines (NCI-H345, MCF-7, SMMC-7721 and Hela) and cells deficient in Bax and/or Bak by shRNA were used to unravel the cascade of events by which S1 promotes apoptosis compared with Bcl-2/Bcl-xL inhibitor ABT-737. We identified that S1 exhibited broader antitumour spectrum than ABT-737 through disruption of more Bcl-2 interactions including Mcl-1/Bak interaction. Moreover, the individual and combined roles of Bax and Bak in S1-induced apoptosis were revealed. Our results showed that S1 induced a Bak-mediated apoptosis. Bak played a predominant role in either S1 or ABT-737-induced apoptosis through the cooperation with Bax on the formation of large oligomers on mitochondrial membrane.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Xue
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shen
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Li
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000819:agonists*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering; D013449:Sulfonamides / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000819:agonists*; D051020:bcl-X Protein / Q000819:agonists*
chemical_list: C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; C501332:ABT-737; D000073:Acenaphthenes; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011758:Pyrroles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein