Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Abstract

AbstractAcute myeloid leukemia (AML) is a disease of malignant proliferation of abnormally or poorly differentiated myeloid cells of the hematopoietic system. The clinical treatments of non-M3 AML are experiencing a lack of effective drugs. V8 is a newly synthesized derivative of the natural flavonoid wogonin, which belongs to the potential anticancer drug, and has shown significant antitumor activityin vitroandin vivo. In this study, we investigated the effects of V8 on AML cell lines and primary AML cells and the underlying mechanisms. The results showed that V8 inhibited the growth and induced the apoptosis of AML cell lines (ME-1, Kasumi-1, and U937) and primary AML cells in a concentration-dependent manner. Meanwhile, we revealed that V8-induced apoptosis was accompanied by mitochondrial injury, such as the reduction of mitochondrial membrane potential and ATP production, activation of endoplasmic reticulum stress (ERS) characterized by GRP78 and caspase-12 expression upregulation. Mechanism studies have shown that V8 induced mitochondrial injury and inhibited mitophagy via elevating the intracellular ROS level. In addition, V8 activated PERK-p-eIF2α-ATF4 and Ire1α-XBP1 pathways and induced apoptosis of AML cells via selectively activating CHOP. Correspondingly, the degree of apoptosis and expression of apoptosis-related proteins were alleviated after the elimination of cytoplasmic ROS with N-Acetyl-L-cysteine (NAC) and knocking out CHOP in the cells by transfection with CHOP shRNA, implicating that mitochondrial injury-triggered upregulation of ROS and CHOP played an important role in V8-induced apoptosis of AML cells. In primary AML cells-bearingNOD/SCIDmice model and U937 cells-inoculatingBALB/cnude mice xenografts transplantation tumor model, administration of V8 markedly prolonged survival time and inhibited the xenografts growth via CHOP-mediated ERSin vivo. In conclusion, our study provides a new insight into the mechanism of V8-induced apoptosis, suggesting the potential of V8 as a promising agent against AML.