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.
Highlights
Cancer stem cells (CSCs) are tumor-initiating cells (TICs) [1, 2] that appear to be the biological basis of treatment failure, due to tumor recurrence and distant metastasis [3,4,5,6,7], leading to poor clinical outcome in cancer patients
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
We show that TPP‐related compounds provide a novel chemical strategy for effectively killing both i) “bulk” cancer cells and ii) CSCs, while minimizing or avoiding off‐target side‐effects in normal cells
Summary
Cancer stem cells (CSCs) are tumor-initiating cells (TICs) [1, 2] that appear to be the biological basis of treatment failure, due to tumor recurrence and distant metastasis [3,4,5,6,7], leading to poor clinical outcome in cancer patients. Circulating tumor cells (CTCs) directly share many key functional properties with CSCs [1,2,3,4,5,6,7]. Recent studies indicate that one unique feature of CSCs is a characteristic increase in mitochondrial mass [8], which may reflect a more strict dependence on mitochondrial function or OXPHOS [9,10]. Several independent lines of evidence support the idea that increased mitochondrial biogenesis or higher levels of mitochondrial protein translation may occur in CSCs [8,9,10,11,12,13,14,15,16,17,18]. Unbiased proteomics analysis directly shows that mitochondrial mass is elevated in CSCs [8]
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