title: Anti-leukemic activity of ubiquinone-based compounds targeting trans-plasma membrane electron transport.
abstract: 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.
authors: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors: Carole
authors: C
authors: Grasso
authors: Lesley
authors: L
authors: Larsen
authors: Melanie
authors: M
authors: McConnell
authors: Robin A J
authors: RA
authors: Smith
authors: Michael V
authors: MV
authors: Berridge
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D010084:Oxidation-Reduction / Q000187:drug effects; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014451:Ubiquinone