Anti-Leukemic Activity of Ubiquinone-Based Compounds Targeting Trans-plasma Membrane Electron Transport

Trans-plasma membrane electron transport (tPMET) is a ubiquinone-dependent cell survival pathway for maintaining intracellular redox homeostasis in rapidly dividing cells. To target this pathway, fifteen ubiquinone-based compounds were designed and synthesized to position at the plasma membrane and disrupt tPMET. We established that quaternary ammonium salt moieties carrying highly hindered, positive electronic charges located to the plasma membrane. A ten-carbon chain linked to these moieties was effective at positioning the redox-active ubiquinone-like function within the lipid bilayer to disrupt tPMET in human leukemic cells (IC₅₀ 9 ± 1 μM). TPMET inhibition alone was not sufficient to induce significant cell death, but positively charged compounds could also enter the cell and disrupt intracellular redox balance, distinct from their effects on mitochondrial electron transport. The synergistic effect of tPMET inhibition plus intracellular redox disruption gave strong antiproliferative activity (IC₅₀ 2 ± 0.2 μM). Positively charged ubiquinone-based compounds inhibit human leukemic cell growth

Anti-Leukemic Activity of Ubiquinone-Based Compounds Targeting Trans-plasma Membrane Electron Transport

Trans-plasma membrane electron transport (tPMET) is a ubiquinone-dependent cell survival pathway for maintaining intracellular redox homeostasis in rapidly dividing cells. To target this pathway, fifteen ubiquinone-based compounds were designed and synthesized to position at the plasma membrane and disrupt tPMET. We established that quaternary ammonium salt moieties carrying highly hindered, positive electronic charges located to the plasma membrane. A ten-carbon chain linked to these moieties was effective at positioning the redox-active ubiquinone-like function within the lipid bilayer to disrupt tPMET in human leukemic cells (IC₅₀ 9 ± 1 μM). TPMET inhibition alone was not sufficient to induce significant cell death, but positively charged compounds could also enter the cell and disrupt intracellular redox balance, distinct from their effects on mitochondrial electron transport. The synergistic effect of tPMET inhibition plus intracellular redox disruption gave strong antiproliferative activity (IC₅₀ 2 ± 0.2 μM). Positively charged ubiquinone-based compounds inhibit human leukemic cell growth

Additional file 2: Figure S1. of Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations

CD133+ and CD133- cells have similar frequency of tumour-initiating cells. Serial dilution of CD133+ and CD133- cell used in sub-cutaneous xenograft. Square, 105 cells; triangle, 104 cells; circle, 103 cells. Average (+/- SD) tumour volume measured over time, 3–5 mice/group. Data representative of 2 independent replicate experiments (PDF 203 kb