A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells

Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Heron F.V. Torquato, Manoel Trindade Rodrigues Junior, Cauê Santos Lima, Roberto Theodoro de Araujo Júnior, Fernanda Talhati, Dhebora Albuquerque Dias, Giselle Zenker Justo, Alice Teixeira Ferreira, Ronaldo Aloise Pilli, Edgar J. Paredes-Gamero
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Alkaloids Canthin-6-one Cell death Apoptosis Necroptosis DNA damage Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/70bf41681ed4460881a6f8a53c9217f0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:70bf41681ed4460881a6f8a53c9217f0
record_format	dspace
spelling	oai:doaj.org-article:70bf41681ed4460881a6f8a53c9217f02021-11-22T04:17:43ZA canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells0753-332210.1016/j.biopha.2021.112439https://doaj.org/article/70bf41681ed4460881a6f8a53c9217f02022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012257https://doaj.org/toc/0753-3322Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids has been extensively studied in different cell types, including leukemic strains. Among the canthin-6-one analogs tested, 10-methoxycanthin-6-one (Mtx-C) showed the highest cytotoxicity in the malignant AML cells Kasumi-1 and KG-1. Thus, we evaluated the cytotoxicity and cell death mechanisms related to Mtx-C using the EC50 (80 µM for Kasumi-1 and 36 µM for KG-1) treatment for 24 h. Our results identify reactive oxygen species production, mitochondrial depolarization, annexin V-FITC/7-AAD double staining, caspase cleave and upregulation of mitochondria-dependent apoptosis proteins (Bax, Bim, Bik, Puma and phosphorylation of p53) for both cell lineages. However, downregulation of Bcl-2 and the simultaneous execution of the apoptotic and necroptotic programs associated with the phosphorylation of the proteins receptor-interacting serine/threonine-protein kinase 3 and mixed lineage kinase domain-like pseudokinase occurred only in Kasumi-1 cells. About the lasted events, Kasumi-1 cell death was inhibited by pharmacological agents such as Zvad-FMK and necrostatin-1. The underlying molecular mechanisms of Mtx-C still include participation in the DNA damage and stress-signaling pathways involving p38 and c-Jun N-terminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules.Heron F.V. TorquatoManoel Trindade Rodrigues JuniorCauê Santos LimaRoberto Theodoro de Araujo JúniorFernanda TalhatiDhebora Albuquerque DiasGiselle Zenker JustoAlice Teixeira FerreiraRonaldo Aloise PilliEdgar J. Paredes-GameroElsevierarticleAlkaloidsCanthin-6-oneCell deathApoptosisNecroptosisDNA damageTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112439- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alkaloids Canthin-6-one Cell death Apoptosis Necroptosis DNA damage Therapeutics. Pharmacology RM1-950
spellingShingle	Alkaloids Canthin-6-one Cell death Apoptosis Necroptosis DNA damage Therapeutics. Pharmacology RM1-950 Heron F.V. Torquato Manoel Trindade Rodrigues Junior Cauê Santos Lima Roberto Theodoro de Araujo Júnior Fernanda Talhati Dhebora Albuquerque Dias Giselle Zenker Justo Alice Teixeira Ferreira Ronaldo Aloise Pilli Edgar J. Paredes-Gamero A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
description	Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids has been extensively studied in different cell types, including leukemic strains. Among the canthin-6-one analogs tested, 10-methoxycanthin-6-one (Mtx-C) showed the highest cytotoxicity in the malignant AML cells Kasumi-1 and KG-1. Thus, we evaluated the cytotoxicity and cell death mechanisms related to Mtx-C using the EC50 (80 µM for Kasumi-1 and 36 µM for KG-1) treatment for 24 h. Our results identify reactive oxygen species production, mitochondrial depolarization, annexin V-FITC/7-AAD double staining, caspase cleave and upregulation of mitochondria-dependent apoptosis proteins (Bax, Bim, Bik, Puma and phosphorylation of p53) for both cell lineages. However, downregulation of Bcl-2 and the simultaneous execution of the apoptotic and necroptotic programs associated with the phosphorylation of the proteins receptor-interacting serine/threonine-protein kinase 3 and mixed lineage kinase domain-like pseudokinase occurred only in Kasumi-1 cells. About the lasted events, Kasumi-1 cell death was inhibited by pharmacological agents such as Zvad-FMK and necrostatin-1. The underlying molecular mechanisms of Mtx-C still include participation in the DNA damage and stress-signaling pathways involving p38 and c-Jun N-terminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules.
format	article
author	Heron F.V. Torquato Manoel Trindade Rodrigues Junior Cauê Santos Lima Roberto Theodoro de Araujo Júnior Fernanda Talhati Dhebora Albuquerque Dias Giselle Zenker Justo Alice Teixeira Ferreira Ronaldo Aloise Pilli Edgar J. Paredes-Gamero
author_facet	Heron F.V. Torquato Manoel Trindade Rodrigues Junior Cauê Santos Lima Roberto Theodoro de Araujo Júnior Fernanda Talhati Dhebora Albuquerque Dias Giselle Zenker Justo Alice Teixeira Ferreira Ronaldo Aloise Pilli Edgar J. Paredes-Gamero
author_sort	Heron F.V. Torquato
title	A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
title_short	A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
title_full	A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
title_fullStr	A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
title_full_unstemmed	A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
title_sort	canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with dna damage in acute myeloid cells
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/70bf41681ed4460881a6f8a53c9217f0
work_keys_str_mv	AT heronfvtorquato acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT manoeltrindaderodriguesjunior acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT cauesantoslima acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT robertotheodorodearaujojunior acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT fernandatalhati acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT dheboraalbuquerquedias acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT gisellezenkerjusto acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT aliceteixeiraferreira acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT ronaldoaloisepilli acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT edgarjparedesgamero acanthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT heronfvtorquato canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT manoeltrindaderodriguesjunior canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT cauesantoslima canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT robertotheodorodearaujojunior canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT fernandatalhati canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT dheboraalbuquerquedias canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT gisellezenkerjusto canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT aliceteixeiraferreira canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT ronaldoaloisepilli canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells AT edgarjparedesgamero canthin6onederivativeinducescelldeathbyapoptosisnecroptosislikewithdnadamageinacutemyeloidcells
_version_	1718418228892401664

A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells

Ejemplares similares