title: Novel insights into the antiproliferative effects and synergism of quercetin and menadione in human leukemia Jurkat T cells.
abstract: The flavonoid quercetin and menadione (vitamin K3) are known as potent apoptogens in human leukemia Jurkat T cells. We explored some underlying mechanisms and the potential relevance of the combination quercetin-menadione for clinical applications. In acute treatments, quercetin manifested a strong antioxidant character, but induced a transient loss of Δψm, likely mediated by opening of the mitochondrial permeability transition pore. After removal of quercetin, persistent mitochondrial hyperpolarization was generated via stimulation of respiratory Complex I. In contrast, menadione-induced Δψm dissipation was only partially and transiently reversed after menadione removal. Results indicate that Ca(2+) release is a necessary event in quercetin-induced cell death and that the survival response to quercetin is delineated within 1h from exposure. Depending on dose, the two agents exhibited either antagonistic or synergistic effects in reducing clonogenicity of Jurkat cells. 24-h combinatorial regimens at equimolar concentrations of 10-15 μM, which are compatible with a clinically achievable (and safe) scheme, reduced cell viability at efficient rates. Altogether, these findings support the idea that the combination quercetin-menadione could improve the outcome of conventional leukemia therapies, and warrant the utility of additional studies to investigate the therapeutic effects of this combination in different cellular or animal models for leukemia.
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania. Electronic address: baran@ifin.nipne.ro.
authors.forename: Irina
authors.initials: I
authors.lastname: Baran
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Diana
authors.initials: D
authors.lastname: Ionescu
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Filippi
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Maria Magdalena
authors.initials: MM
authors.lastname: Mocanu
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Adrian
authors.initials: A
authors.lastname: Iftime
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Ramona
authors.initials: R
authors.lastname: Babes
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Ioana Teodora
authors.initials: IT
authors.lastname: Tofolean
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Irimia
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Goicea
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Valentin
authors.initials: V
authors.lastname: Popescu
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Dimancea
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Andrei
authors.initials: A
authors.lastname: Neagu
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Department of Biophysics, 8 Eroii Sanitari, 050474 Bucharest, Romania.
authors.forename: Constanta
authors.initials: C
authors.lastname: Ganea
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D012402:Rotenone; D009243:NAD; D024483:Vitamin K 3; D011794:Quercetin
keywords: Leukemia; Menadione; Mitochondrial depolarization/hyperpolarization; Quercetin; Reactive oxygen species; Rotenone