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DNA Damage-Inducing 10-Methoxy-canthin-6-one (Mtx-C) Promotes Cell Cycle Arrest in G2/M and Myeloid Differentiation of Acute Myeloid Leukemias and Leukemic Stem Cells.
Torquato, Heron F V; Rodrigues Junior, Manoel Trindade; Lima, Cauê Santos; de Araujo Júnior, Roberto Theodoro; Soares, Caio C S P; Domiciano, André Tarsis; de Morais, Rafael Leite Tavares; Rosolen, Daiane; Cavalli, Luciane Regina; Santos-Filho, Osvaldo Andrade; Justo, Giselle Zenker; Pilli, Ronaldo Aloise; Paredes-Gamero, Edgar J.
Afiliación
  • Torquato HFV; Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS 79070-900, Brazil.
  • Rodrigues Junior MT; Instituto de Química, Universidade Estadual de Campinas, Campinas, SP 13084-971, Brazil.
  • Lima CS; Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • de Araujo Júnior RT; Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • Soares CCSP; Instituto de Química, Universidade Estadual de Campinas, Campinas, SP 13084-971, Brazil.
  • Domiciano AT; Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • de Morais RLT; Departamento de Biofísica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • Rosolen D; Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, Brazil.
  • Cavalli LR; Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, Brazil.
  • Santos-Filho OA; Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D.C. 20007, United States.
  • Justo GZ; Laboratório de Modelagem Molecular e Biologia Estrutural Computacional, Instituto de Pesquisas de Produtos Naturais Walter Mors, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373 - Bloco H, Cidade Universitária, Rio de Janeiro 21941-599, Brazil.
  • Pilli RA; Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • Paredes-Gamero EJ; Instituto de Química, Universidade Estadual de Campinas, Campinas, SP 13084-971, Brazil.
ACS Omega ; 9(35): 37343-37354, 2024 Sep 03.
Article en En | MEDLINE | ID: mdl-39246489
ABSTRACT
Synthetic 10-methoxy-canthin-6-one (Mtx-C), an alkaloid derivative, exhibits cytotoxic effects against acute myeloid cells (AMLs) and leukemic stem cells (LSCs) at a concentration of approximately 60 µM. However, the antitumor mechanism of Mtx-C in AMLs and LSCs remains elusive. Using Mtx-C at concentrations with low cytotoxicity (2-4 µM) for 72 h, we observed cell arrest with the accumulation of cells in the G2/M phase of the cell cycle. This effect was controlled by cyclin B1 expression and induction of the DNA damage cascade characterized by ATM, ATR, Chk1/2, p53, and H2A.X phosphorylation. Molecular docking analysis confirmed Mtx-C as a DNA intercalator. Moreover, the expression of inhibitors of cyclin-dependent kinases, including p21 (Cip1) and p27 (Kip1), increased. In addition, several miRNAs that are considered oncosuppressors were regulated by Mtx-C in Kasumi-1 cells. Finally, concomitant with cell cycle arrest, the underlying molecular mechanisms of Mtx-C in AML cells include myeloid differentiation, as evidenced by the increased expression of PU.1, myeloperoxidase, CD15, CD11b, and CD14 in the AML and LSC populations with the participation of p38 mitogen-activated protein kinase. Thus, we showed that Mtx-C simultaneously induced cell cycle arrest and myeloid differentiation in AML lineages and in the LSC population, providing insights into new therapeutic alternatives for the treatment of AML based on naturally occurring molecules.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Omega Año: 2024 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Omega Año: 2024 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos