Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells

dc.creatorRodrigues, Ana Carolina Borges da Cruz
dc.creatorBomfim, Larissa Mendes
dc.creatorNeves, Sara Parente
dc.creatorSoares, Milena Botelho Pereira
dc.creatorDias, Rosane Borges
dc.creatorValverde, Ludmila de Faro
dc.creatorRocha, Clarissa Araújo Gurgel
dc.creatorCosta, Emmanoel Vilaça
dc.creatorSilva, Felipe Moura Araujo da
dc.creatorGomes, Waldireny Rocha
dc.creatorKoolen, Hector Henrique Ferreira
dc.creatorBezerra, Daniel Pereira
dc.date2021-09-27T10:30:02Z
dc.date2021-09-27T10:30:02Z
dc.date2021
dc.date.accessioned2023-09-26T20:53:23Z
dc.date.available2023-09-26T20:53:23Z
dc.identifierRODRIGUES, Ana Carolina Borges da Cruz et al. Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells. Biomedicine and Pharmacotherapy, v. 142, p. 1-13, 2021.
dc.identifier0753-3322
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/49165
dc.identifier10.1016/j.biopha.2021.112034
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8865664
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM)
dc.descriptionFundação de Amparo à Pesquisa do Estado da Bahia (FAPESB)
dc.descriptionAcute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TGand 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsopen access
dc.subjectLeucemia mieloide aguda
dc.subjectEstresse oxidativo
dc.subjectTioredoxina
dc.subjectCélulas HL-60
dc.subjectApoptose
dc.subjectTingenone
dc.subject22-hydroxytingenone
dc.subjectThioredoxin
dc.subjectOxidative stress
dc.subjectApoptosis
dc.subjectAML
dc.titleTingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells
dc.typeArticle


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