A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells
| Autor: | Heron F.V. Torquato, Fernanda Talhati, Edgar J. Paredes-Gamero, Giselle Z. Justo, Alice T. Ferreira, Cauê Santos Lima, Ronaldo A. Pilli, Manoel Trindade Rodrigues Junior, Roberto T. Araujo Júnior, Dhébora Albuquerque Dias |
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| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
DNA damage MAP Kinase Signaling System Necroptosis Cell Antineoplastic Agents Apoptosis RM1-950 p38 Mitogen-Activated Protein Kinases Indole Alkaloids Alkaloids Annexin Cell Line Tumor medicine Humans Protein kinase A Pharmacology Cell Death Chemistry Myeloid leukemia General Medicine Leukemia Myeloid Acute medicine.anatomical_structure Canthin-6-one Cancer research Therapeutics. Pharmacology Reactive Oxygen Species Carbolines DNA Damage |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 145, Iss, Pp 112439-(2022) |
| ISSN: | 1950-6007 |
| Popis: | 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-methoxycanthin-6-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 µM for Kasumi-1 and 36 µM 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 N-terminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules. |
| Databáze: | OpenAIRE |
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