In Vitro Study of Cytotoxic Mechanisms of Alkylphospholipids and Alkyltriazoles in Acute Lymphoblastic Leukemia Models
Larissa de Oliveira Passos Jesus,
Aline Aparecida de Souza,
Heron Fernandes Vieira Torquato,
Vanessa Silva Gontijo,
Rossimirian Pereira de Freitas,
Tarsis Ferreira Gesteira,
Vivien Jane Coulson-Thomas,
Ricardo José Soares Torquato,
Aparecida Sadae Tanaka,
Edgar Julian Paredes-Gamero,
Wagner Alves de Souza Judice
Affiliations
Larissa de Oliveira Passos Jesus
Interdisciplinary Center for Biochemical Research, University of Mogi das Cruzes (UMC), Mogi das Cruzes 08780-911, SP, Brazil
Aline Aparecida de Souza
Interdisciplinary Center for Biochemical Research, University of Mogi das Cruzes (UMC), Mogi das Cruzes 08780-911, SP, Brazil
Heron Fernandes Vieira Torquato
Faculty of Pharmacy, Centro Universitário Braz Cubas (UBC), Mogi das Cruzes 08773-380, SP, Brazil
Vanessa Silva Gontijo
Phytochemistry and Medicinal Chemistry Laboratory (LFQM), Institute of Chemistry, Federal University of Alfenas (UNIFAL), Alfenas 37130-000, MG, Brazil
Rossimirian Pereira de Freitas
Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais (UFMG), Belo Horizonte 31270-901, MG, Brazil
Tarsis Ferreira Gesteira
College of Optometry, University of Houston, Houston, TX 77204, USA
Vivien Jane Coulson-Thomas
College of Optometry, University of Houston, Houston, TX 77204, USA
Ricardo José Soares Torquato
Department of Biochemistry, Federal University of São Paulo, São Paulo (UNIFESP), São Paulo 04044-020, SP, Brazil
Aparecida Sadae Tanaka
Department of Biochemistry, Federal University of São Paulo, São Paulo (UNIFESP), São Paulo 04044-020, SP, Brazil
Edgar Julian Paredes-Gamero
Faculty of Pharmaceutical Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul (UFMS), Campo Grande 79070-900, MS, Brazil
Wagner Alves de Souza Judice
Interdisciplinary Center for Biochemical Research, University of Mogi das Cruzes (UMC), Mogi das Cruzes 08780-911, SP, Brazil
This 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.
