9 research outputs found
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
(IC<sub>50</sub> 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 (IC<sub>50</sub> 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
(IC<sub>50</sub> 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 (IC<sub>50</sub> 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, 3â5 mice/group. Data representative of 2 independent replicate experiments (PDF 203Â kb
The effect of PFC plus carbogen and carbogen alone on survival of mice with intracranial tumours who received a single dose of whole brain radiation.
<p>Kaplan Meier curves were compiled from 3 separate experiments. Mice were randomly assigned to groups of 5 mice. Mice were left untreated (black line), given 4.5Gy of radiation (red line), breathing carbogen (95%O<sub>2</sub>/5%CO<sub>2</sub>) for 1h immediately prior to irradiation (green line) or injected IV with 1.5cc/kg of a 40% PFC emulsion in addition to breathing carbogen for one hour immediately prior to irradiation (blue line). Only data from animals that died from tumour progression were used. Data from animals that died from other causes were excluded.</p
Irradiation setup for whole brain irradiation of mice.
<p>(A) The mouse is anaesthetized and positioned in a Falcon tube (B) inside a 2 cm thick lead shielding device (C) inside plastic rings (D) inside the aluminium cylinder in the Gammacell 3000 Elan irradiator. (E) Diagrammatic representation of the irradiation setup. This setup allowed us only to do whole brain irradiation; we could not irradiate subcutaneous tumors.</p
Effect of PFC/carbogen and carbogen alone on hypoxia in subcutaneous mouse glioma tumours.
<p>Animals were divided into groups of 5 mice each. (A) Untreated control mice; (B) mice exposed to both PFC emulsions and carbogen and (C) mice exposed to carbogen alone. Tumor-bearing mice were injected IV with 1.5cc/kg of a 40% PFC emulsion and hypoxia was measured using pimonidazole-HCL (PIM). Mice that received carbogen (95%O<sub>2</sub>/5%CO<sub>2</sub>) for 1h were placed in an air-tight chamber. Photos are representative of 2 separate experiments with 5 mice in each group.</p
Statistical data for Fig 5.
<p>Statistical data for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184250#pone.0184250.g005" target="_blank">Fig 5</a>.</p
Effect of PFC/carbogen and carbogen alone on hypoxia in intracranial mouse glioma tumours.
<p>Animals were divided into groups of 5 mice each. A. Untreated control mice; B. Mice exposed to PFC emulsions; C. Mice exposed to carbogen and D. Mice exposed to both PFC emulsions and carbogen. Tumor-bearing mice were injected IV with 1.5cc/kg of a 40% PFC emulsion and hypoxia was measured using pimonidazole-HCL (PIM). Mice that received carbogen (95%O<sub>2</sub>/5%CO<sub>2</sub>) for 1h were placed in an air-tight chamber. Photos are representative of 3 separate experiments.</p
Different hypoxia levels in intracranial tumours of untreated control mice in the same experiment.
<p><b>(</b>A) and (C): day 14 after implantation; (B) and (D): day 16 after implantation. Photographs are from one experiment with 4 mice (A-D).</p