In vitro study of cytotoxic mechanisms of alkylphospholipids and alkyltriazoles in acute lymphoblastic leukemia models

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dc.creatorLarissa de Oliveira Passos Jesus
dc.creatorAline Aparecida de Souza
dc.creatorHeron Fernandes Vieira Torquato
dc.creatorVanessa Silva Gontijo
dc.creatorRossimiriam Pereira de Freitas
dc.creatorTarsis Ferreira Gesteira
dc.creatorVivien Jane Coulson-Thomas
dc.creatorRicardo José Soares Torquato
dc.creatorAparecida Sadae Tanaka
dc.creatorEdgar Julian Paredes-Gamero
dc.creatorWagner Alves de Souza Judice
dc.date.accessioned2024-08-05T17:44:46Z
dc.date.accessioned2025-09-09T00:07:54Z
dc.date.available2024-08-05T17:44:46Z
dc.date.issued2022
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.description.sponsorshipOutra Agência
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.3390/molecules27238633
dc.identifier.issn1420-3049
dc.identifier.urihttps://hdl.handle.net/1843/72626
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofMolecules
dc.rightsAcesso Aberto
dc.subjectAgentes antineoplásicos
dc.subjectLeucemia linfoblástica
dc.subjectCélulas mortas
dc.subjectDinâmica molecular
dc.subject.otherAlkylphospholipids
dc.subject.otherAlkyltriazoles
dc.subject.otherCell death
dc.subject.otherAcute lymphoblastic leukemia
dc.subject.otherCathepsin inhibition
dc.titleIn vitro study of cytotoxic mechanisms of alkylphospholipids and alkyltriazoles in acute lymphoblastic leukemia models
dc.typeArtigo de periódico
local.citation.issue23
local.citation.volume27
local.description.resumoThis study investigates the efficacy of miltefosine, alkylphospholipid, and alkyltriazolederivative compounds against leukemia lineages. The cytotoxic effects and cellular and molecular mechanisms of the compounds were investigated. The inhibitory potential and mechanism of inhibition of cathepsins B and L, molecular docking simulation, molecular dynamics and binding free energy evaluation were performed to determine the interaction of cathepsins and compounds. Among the 21 compounds tested, C9 and C21 mainly showed cytotoxic effects in Jurkat and CCRF-CEM cells, two human acute lymphoblastic leukemia (ALL) lineages. Activation of induced cell death by C9 and C21 with apoptotic and necrosis-like characteristics was observed, including an increase in annexin-V+propidium iodide−, annexin-V+propidium iodide+, cleaved caspase 3 and PARP, cytochrome c release, and nuclear alterations. Bax inhibitor, Z-VAD-FMK, pepstatin, and necrostatin partially reduced cell death, suggesting that involvement of the caspase-dependent and -independent mechanisms is related to cell type. Compounds C9 and C21 inhibited cathepsin L by a noncompetitive mechanism, and cathepsin B by a competitive and noncompetitive mechanism, respectively. Complexes cathepsin-C9 and cathepsin-C21 exhibited significant hydrophobic interactions, water bridges, and hydrogen bonds. In conclusion, alkyltriazoles present cytotoxic activity against acute lymphoblastic lineages and represent a promising scaffold for the development of molecules for this application.
local.identifier.orcidhttps://orcid.org/0000-0001-9004-4872
local.identifier.orcidhttps://orcid.org/0000-0002-9480-9657
local.identifier.orcidhttps://orcid.org/0000-0003-1674-818X
local.identifier.orcidhttps://orcid.org/0000-0001-6974-3724
local.identifier.orcidhttps://orcid.org/0000-0002-0136-0986
local.identifier.orcidhttps://orcid.org/0000-0002-5848-0225
local.identifier.orcidhttps://orcid.org/0000-0001-9407-805X
local.identifier.orcidhttps://orcid.org/0000-0003-3686-8402
local.identifier.orcidhttps://orcid.org/0000-0002-1608-9105
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.mdpi.com/1420-3049/27/23/8633

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