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

Aging
Bela OzsvariMichael P Lisanti

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

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Jun 24, 2009·Expert Opinion on Biological Therapy·Alessandro ScopellitiGiorgio Stassi
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May 26, 2016·Breast Cancer Research : BCR·Maria Peiris-PagèsMichael P Lisanti

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Citations

Nov 16, 2018·British Journal of Pharmacology·Luigi LeanzaIldiko Szabo
Feb 28, 2020·Experimental Biology and Medicine·Yao-An ShenYau-Huei Wei
Oct 21, 2019·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Xian-Liang DuanJing Luan
Aug 8, 2021·International Journal of Molecular Sciences·Joseph E FriedlanderHui Feng

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