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

Author(s)

Torquato, V, Heron F. ; Rodrigues Junior, Manoel Trindade ^[1] ; Lima, Caue Santos ^[2] ; de Araujo Junior, Roberto Theodoro ^{[2, 3]} ; Talhati, Fernanda ^[3] ; Dias, Dhebora Albuquerque ^[4] ; Justo, Giselle Zenker ^[2] ; Ferreira, Alice Teixeira ^[5] ; Pilli, Ronaldo Aloise ^[1] ; Paredes-Gamero, Edgar J. ^{[2, 4]}

Affiliation

^[1] Univ Estadual Campinas, Inst Quim, BR-13084971 Campinas, SP - Brazil

^[2] Torquato, Heron F., V, Univ Fed Sao Paulo, Dept Bioquim, R Tres de Maio 100, BR-04044020 Sao Paulo, SP - Brazil

^[3] Torquato, Heron F., V, Ctr Univ Braz Cubas, Fac Farm, BR-08773380 Mogi Das Cruzes, SP - Brazil

^[4] Torquato, Heron F., V, Univ Fed Mato Grosso do Sul, Fac Ciencias Farm Alimentos & Nutr, BR-79070900 Campo Grande, MS - Brazil

^[5] Univ Fed Sao Paulo, Dept Biofis, R Tres de Maio 100, BR-04044020 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: BIOMEDICINE & PHARMACOTHERAPY; v. 145, JAN 2022.
• Web of Science Citations: 0

Abstract

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-methoxycanthin6-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 mu M for Kasumi-1 and 36 mu M 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 Nterminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules. (AU)

• FAPESP's process: 16/18990-5 - Studies of cellular and molecular mechanisms of tumor cell death induced by antimicrobial peptides
• Grantee: Edgar Julian Paredes-Gamero
• Support Opportunities: Regular Research Grants