• Login
    View Item 
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsProfilesView

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    Exploiting mitochondrial targeting signal(s), TPP and bis-TPP, for eradicating cancer stem cells (CSCs).

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    n6f4cLqfbgdMj5Bwf.pdf
    Size:
    3.440Mb
    Format:
    PDF
    Description:
    Full text, Open Access article
    Download
    Authors
    Ozsvari, Bela
    Sotgia, Federica
    Lisanti, Michael P
    Affiliation
    Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Mancheste
    Issue Date
    2018-02-19
    
    Metadata
    Show full item record
    Abstract
    Tri-phenyl-phosphonium (TPP) is a non-toxic chemical moiety that functionally behaves as a mitochondrial targeting signal (MTS) in living cells. Here, we explored the hypothesis that TPP-related compounds could be utilized to inhibit mitochondria in cancer stem cells (CSCs). We randomly selected 9 TPP-related compounds for screening, using an ATP depletion assay. Based on this approach, five compounds were identified as "positive hits"; two had no detectable effect on ATP production. Remarkably, this represents a >50% hit rate. We validated that the five positive hit compounds all inhibited oxygen consumption rates (OCR), using the Seahorse XFe96 metabolic flux analyzer. Interestingly, these TPP-related compounds were non-toxic and had little or no effect on ATP production in normal human fibroblasts, but selectively targeted adherent "bulk" cancer cells. Finally, these positive hit compounds also inhibited the propagation of CSCs in suspension, as measured functionally using the 3D mammosphere assay. Therefore, these TPP-related compounds successfully inhibited anchorage-independent growth, which is normally associated with a metastatic phenotype. Interestingly, the most effective molecule that we identified contained two TPP moieties (i.e., bis-TPP). More specifically, 2-butene-1,4-bis-TPP potently and selectively inhibited CSC propagation, with an IC-50 < 500 nM. Thus, we conclude that the use of bis-TPP, a "dimeric" mitochondrial targeting signal, may be a promising new approach for the chemical eradication of CSCs. Future studies on the efficacy of 2-butene-1,4-bis-TPP and its derivatives are warranted. In summary, we show that TPP-related compounds provide a novel chemical strategy for effectively killing both i) "bulk" cancer cells and ii) CSCs, while specifically minimizing or avoiding off-target side-effects in normal cells. These results provide the necessary evidence that "normal" mitochondria and "malignant" mitochondria are truly biochemically distinct, removing a significant barrier to therapeutically targeting cancer metabolism.
    Citation
    Exploiting mitochondrial targeting signal(s), TPP and bis-TPP, for eradicating cancer stem cells (CSCs). 2018, 10(2): 229-240 Aging (Albany NY)
    Journal
    Aging
    URI
    http://hdl.handle.net/10541/620890
    DOI
    10.18632/aging.101384
    PubMed ID
    29466249
    Type
    Article
    Language
    en
    ISSN
    1945-4589
    ae974a485f413a2113503eed53cd6c53
    10.18632/aging.101384
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

    entitlement

    Related articles

    • Dodecyl-TPP Targets Mitochondria and Potently Eradicates Cancer Stem Cells (CSCs): Synergy With FDA-Approved Drugs and Natural Compounds (Vitamin C and Berberine).
    • Authors: De Francesco EM, Ózsvári B, Sotgia F, Lisanti MP
    • Issue date: 2019
    • Targeting flavin-containing enzymes eliminates cancer stem cells (CSCs), by inhibiting mitochondrial respiration: Vitamin B2 (Riboflavin) in cancer therapy.
    • Authors: Ozsvari B, Bonuccelli G, Sanchez-Alvarez R, Foster R, Sotgia F, Lisanti MP
    • Issue date: 2017 Dec 16
    • Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs).
    • Authors: Fiorillo M, Tóth F, Sotgia F, Lisanti MP
    • Issue date: 2019 Apr 19
    • First-in-class candidate therapeutics that target mitochondria and effectively prevent cancer cell metastasis: mitoriboscins and TPP compounds.
    • Authors: Ózsvári B, Sotgia F, Lisanti MP
    • Issue date: 2020 May 24
    • Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).
    • Authors: Fiorillo M, Lamb R, Tanowitz HB, Cappello AR, Martinez-Outschoorn UE, Sotgia F, Lisanti MP
    • Issue date: 2016 Aug
    DSpace software (copyright © 2002 - 2025)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.