Role of 2′-Hydroxycinnamaldehyde In The Induction of Apoptosis Via A Reactive Oxygen Species-Dependent JNK Pathway in Human Promyelocytic HL-60 Leukemia Cells

Abstract Background: Because the role and molecular mechanism of 2′-hydroxycinnamaldehyde (2′-HCA) in human leukemia need to be clarified, we provide detailed insights into the mechanism underlying the anti-proliferative properties of 2′-HCA in acute myeloid leukemia (AML).Methods: We performed MTT assay to examine the cytotoxic effect of 2′-HCA. 2′-HCA-induced apoptotic pathway was demonstrated by annexin V-FITC/ propidium iodide double staining, DAPI staining for DNA fragmentation detection, and western blot analysis. ROS generation, intracellular glutathione (GSH) level, and intracellular protein thiols (PSH) were detected to investigated the mechanism of 2′-HCA-related apoptosis. Xenograft animal model was used to evaluate anti-tumor activities of 2′-HCA.Results: The present study demonstrated that 2′-HCA induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways. 2′-HCA also induced the activation of JNK and the pharmacological inhibition of JNK effectively prevented 2′-HCA-induced apoptosis and AP-1-DNA binding. In addition, 2′-HCA resulted in the accumulation of ROS and depletion of intracellular GSH and PSH in HL-60 cells. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2′-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine, pro-apoptotic proteins, and PCNA protein expression. Conclusion: Our findings suggest that 2′-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia.