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  3. 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

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

  • ACS Omega. 2024 Aug 22;9(35):37343-37354. doi: 10.1021/acsomega.4c05435.
Heron F V Torquato 1,  Manoel Trindade Rodrigues Junior 2,  Cauê Santos Lima 3,  Roberto Theodoro de Araujo Júnior 3,  Caio C S P Soares 2,  André Tarsis Domiciano 3,  Rafael Leite Tavares de Morais 4,  Daiane Rosolen 5,  Luciane Regina Cavalli 5 6,  Osvaldo Andrade Santos-Filho 7,  Giselle Zenker Justo 3,  Ronaldo Aloise Pilli 2,  Edgar J Paredes-Gamero 1 3
Affiliations

Affiliations

  • 1 Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS 79070-900, Brazil.
  • 2 Instituto de Química, Universidade Estadual de Campinas, Campinas, SP 13084-971, Brazil.
  • 3 Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • 4 Departamento de Biofísica, Universidade Federal de São Paulo, R. Três de Maio 100, São Paulo, SP 04044-020, Brazil.
  • 5 Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, Brazil.
  • 6 Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D.C. 20007, United States.
  • 7 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.
PMID: 39246489 DOI: 10.1021/acsomega.4c05435
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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