title: Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner.
abstract: BACKGROUND
  Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its in vitro and in vivo efficacy against TICs.
  
  
  METHODS
  The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. In vivo efficacy was studied by grafting NeuTL TICs to form syngeneic tumours.
  
  
  RESULTS
  Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2(high) tumours derived from breast TICs by inducing apoptosis in tumour cells.
  
  
  CONCLUSIONS
  These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells.
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. bing.yan@griffithuni.edu.au.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. marina.stantic@ki.se.
authors.forename: Marina
authors.initials: M
authors.lastname: Stantic
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. renata.zob@gmail.con.|Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic. renata.zob@gmail.con.
authors.forename: Renata
authors.initials: R
authors.lastname: Zobalova
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. a.bezawork-geleta@griffith.edu.au.
authors.forename: Ayenachew
authors.initials: A
authors.lastname: Bezawork-Geleta
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. pfm.stapelber@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Stapelberg
authors.affiliation: The Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, Czech Republic. jan.stursa@gmail.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic. prokopovak@ibt.cas.cz.
authors.forename: Katerina
authors.initials: K
authors.lastname: Prokopova
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. l.dong@griffith.edu.au.
authors.forename: Lanfeng
authors.initials: L
authors.lastname: Dong
authors.affiliation: School of Medical Science, Griffith University, Southport, Qld, 4222, Australia. j.neuzil@griffith.edu.au.|Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, 142 20, Czech Republic. j.neuzil@griffith.edu.au.
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D042963:Electron Transport Complex II / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D018874:Spheroids, Cellular; D024505:Tocopherols / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D042963:Electron Transport Complex II; D024505:Tocopherols