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 ...Continue Reading
References
Dec 27, 2005·Current Opinion in Genetics & Development·Mei Zhang, Jeffrey M Rosen
Feb 26, 2008·The Biochemical Journal·Meredith F RossMichael P Murphy
Jun 24, 2009·Expert Opinion on Biological Therapy·Alessandro ScopellitiGiorgio Stassi
Jul 1, 2010·Stem Cell Research & Therapy·Julie M Chandler, Eric Lagasse
Aug 6, 2013·Current Pathobiology Reports·Maria Giovanna FrancipaneEric Lagasse
Nov 22, 2014·Oncotarget·Rebecca LambFederica Sotgia
Jan 28, 2015·Oncotarget·Rebecca LambMichael P Lisanti
Jun 19, 2015·Oncotarget·Rebecca LambMichael P Lisanti
Jun 19, 2015·Oncotarget·Arianna De LucaFederica Sotgia
Sep 5, 2015·Cell Stem Cell·Michael D BrooksMax S Wicha
Oct 1, 2015·Oncotarget·Gillian FarnieMichael P Lisanti
Oct 1, 2015·Oncotarget·Rebecca LambMichael P Lisanti
May 4, 2016·Oncotarget·Marco FiorilloMichael P Lisanti
Nov 3, 2016·Nature Reviews. Clinical Oncology·Ubaldo E Martinez-OutschoornMichael P Lisanti
May 26, 2016·Breast Cancer Research : BCR·Maria Peiris-PagèsMichael P Lisanti
Jun 28, 2016·Aging·Marco FiorilloMichael P Lisanti
Jan 1, 2017·Oncotarget·Gloria BonuccelliMichael P Lisanti
Feb 23, 2017·Oncotarget·Gloria BonuccelliMichael P Lisanti
Apr 16, 2017·Oncotarget·Marco FiorilloMichael P Lisanti
Sep 17, 2017·Oncotarget·Ernestina Marianna De FrancescoMichael P Lisanti
Oct 29, 2017·Aging·Bela OzsvariMichael P Lisanti
Citations
Nov 16, 2018·British Journal of Pharmacology·Luigi LeanzaIldiko Szabo
Sep 28, 2018·Cell Cycle·Federica SotgiaMichael P Lisanti
Feb 28, 2020·Experimental Biology and Medicine·Yao-An ShenYau-Huei Wei
Jul 18, 2019·Aging·Maria Peiris-PagèsMichael P Lisanti
May 27, 2020·Aging·Béla ÓzsváriMichael P Lisanti
Aug 24, 2019·Frontiers in Oncology·Ernestina Marianna De FrancescoMichael P Lisanti
Jan 30, 2020·Journal of Cellular and Molecular Medicine·Mengmeng LiXiaoyong Wang
Oct 13, 2020·Frontiers in Oncology·Béla ÓzsváriMichael P Lisanti
Sep 18, 2020·Bioorganic Chemistry·Lu MaYuqing Zhao
Oct 21, 2019·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Xian-Liang DuanJing Luan
May 1, 2021·Antibiotics·Julia A PavlovaNatalia V Sumbatyan
Jul 3, 2021·Polymers·Rúben FariaDiana Costa
Aug 8, 2021·International Journal of Molecular Sciences·Joseph E FriedlanderHui Feng
Aug 17, 2021·Frontiers in Oncology·Camillo SargiacomoMichael P Lisanti
Jun 12, 2019·Inorganic Chemistry·How Chee OngFelipe García
Apr 20, 2019·Analytical Chemistry·Huihui ZhangHongping Zhou