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

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.

Automated summary

The natural product 10-methoxycanthin6-one (Mtx-C) showed high cytotoxicity in malignant AML cells Kasumi-1 and KG-1 by inducing mitochondrial-related apoptosis. Additionally, Mtx-C was able to simultaneously execute apoptotic and necrotic programs in Kasumi-1 cells, offering a promising opportunity for the development of new anti-leukemic molecules.