title: Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells.
abstract: A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics.
authors.affiliation: NanoBioMAv, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Avenida dos Estados 5001, Bairro Bangu, 09210-580 Santo André, SP, Brazil.
authors.forename: Felipe S
authors.initials: FS
authors.lastname: Pessoto
authors.affiliation: NanoBioMAv, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Avenida dos Estados 5001, Bairro Bangu, 09210-580 Santo André, SP, Brazil ; Departamento de Biologia Molecular, Universidade Federal de São Paulo, Rua 3 de Maio 100, Vila Clementino, 04044-020 São Paulo, SP, Brazil.
authors.forename: Cesar H
authors.initials: CH
authors.lastname: Yokomizo
authors.affiliation: NanoBioMAv, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Avenida dos Estados 5001, Bairro Bangu, 09210-580 Santo André, SP, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Prieto
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Cleverton S
authors.initials: CS
authors.lastname: Fernandes
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Silva
authors.affiliation: Instituto de Química-Universidade Federal do Rio de Janeiro (IQ-UFRJ), Edifício do Centro de Tecnologia, Bloco A, Cidade Universitária, 21.941-909 Rio de Janeiro, RJ, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Kaiser
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Ernani A
authors.initials: EA
authors.lastname: Basso
authors.affiliation: NanoBioMAv, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Avenida dos Estados 5001, Bairro Bangu, 09210-580 Santo André, SP, Brazil.
authors.forename: Iseli L
authors.initials: IL
authors.lastname: Nantes
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D007211:Indoles; C511311:NSC73306; D013438:Sulfhydryl Compounds; D013882:Thiosemicarbazones; D005978:Glutathione; C038699:acetophenone