Chung Kyung-Sook, Yoo Chae-Bin, Lee Jeong-Hun, Lee Hwi-Ho, Park Sang-Eun, Han Hee-Soo, Lee Su-Yeon, Kwon Byoung-Mok, Choi Jung-Hye, Lee Kyung-Tae
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Korea.
Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Korea.
Pharmaceutics. 2021 Oct 26;13(11):1794. doi: 10.3390/pharmaceutics13111794.
The present study demonstrated that 2'-hydroxycinnamaldehyde (2'-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome release into the cytosol, (4) loss of mitochondrial membrane potential (Δ), and (5) caspase activation. 2'-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2'-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2'-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2'-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2'-HCA-induced intrinsic apoptosis. 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 and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, 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.
本研究表明，2'-羟基肉桂醛（2'-HCA）通过激活线粒体途径诱导人早幼粒细胞白血病HL-60细胞凋亡，这些途径包括：（1）Bim和Bax从细胞质转位至线粒体；（2）Bcl-2蛋白表达下调；（3）细胞色素c释放到细胞质中；（4）线粒体膜电位（ΔΨm）丧失；（5）半胱天冬酶激活。2'-HCA还诱导HL-60细胞中c-Jun氨基末端激酶（JNK）和细胞外信号调节激酶1/2（ERK1/2）的激活。JNK的药理学和基因抑制有效预防了2'-HCA诱导的细胞凋亡和激活蛋白-1（AP-1）与DNA的结合。此外，2'-HCA导致HL-60细胞中活性氧（ROS）积累、细胞内谷胱甘肽（GSH）和蛋白质巯基（PSH）耗竭。NAC处理消除了2'-HCA诱导的JNK磷酸化、AP-1与DNA的结合以及Bim线粒体转位，表明氧化应激可能是2'-HCA诱导的内源性凋亡所必需的。接种HL-60白血病细胞的异种移植小鼠表明，腹腔注射2'-HCA可通过增加TUNEL染色、硝基酪氨酸和促凋亡蛋白的表达水平，但降低增殖细胞核抗原（PCNA）蛋白表达来抑制肿瘤生长。综上所述，我们的研究结果表明，2'-HCA通过ROS依赖的JNK途径诱导细胞凋亡，可被视为白血病的潜在治疗药物。
