Brassinin Induces Apoptosis, Autophagy, and Paraptosis via MAPK Signaling Pathway Activation in Chronic Myelogenous Leukemia Cells

SIMPLE SUMMARY: Cell death was once thought of as two distinct processes involving mainly apoptosis or necrosis. In recent years, several different forms of cell death have gained importance, such as autophagy, paraptosis, and ferroptosis. Brassinin (BSN) is a phytoalexin identified from Cruciferase vegetables (Brassica) and various pharmacological properties have been reported. However, the efficacy of BSN for chronic myelogenous leukemia has not been elucidated. In our study, we confirmed whether BSN modulates the different cell death processes including apoptosis, autophagy, and paraptosis in chronic myelogenous leukemia cells. In addition, we confirmed that BSN promotes the activation of the MAPK signaling pathway. In this study, BSN could stimulate the activation of apoptosis, autophagy, and paraptosis by modulating the MAPK signaling cascade. ABSTRACT: Brassinin (BSN), a potent phytoalexin found in cruciferous vegetables, has been found to exhibit diverse anti-neoplastic effects on different cancers. However, the impact of BSN on chronic myelogenous leukemia (CML) cells and the possible mode of its actions have not been described earlier. We investigated the anti-cytotoxic effects of BSN on the KBM5, KCL22, K562, and LAMA84 CML cells and its underlying mechanisms of action in inducing programmed cell death. We noted that BSN could induce apoptosis, autophagy, and paraptosis in CML cells. BSN induced PARP cleavage, subG1 peak increase, and early apoptosis. The potential action of BSN on autophagy activation was confirmed by an LC3 expression and acridine orange assay. In addition, BSN induced paraptosis through increasing the reactive oxygen species (ROS) production, mitochondria damage, and endoplasmic reticulum (ER) stress. Moreover, BSN promoted the activation of the MAPK signaling pathway, and pharmacological inhibitors of this signaling pathway could alleviate all three forms of cell death induced by BSN. Our data indicated that BSN could initiate the activation of apoptosis, autophagy, and paraptosis through modulating the MAPK signaling pathway.