Tricetin Induces Apoptosis of Human Leukemic HL-60 Cells through a Reactive Oxygen Species-Mediated c-Jun N-Terminal Kinase Activation Pathway

被引:20
作者
Chien, Ming-Hsien [1 ,2 ]
Chow, Jyh-Ming [3 ]
Lee, Wei-Jiunn [2 ,4 ]
Chen, Hui-Yu [5 ]
Tan, Peng [1 ]
Wen, Yu-Ching [4 ,6 ]
Lin, Yung-Wei [1 ,6 ]
Hsiao, Pei-Ching [7 ,8 ]
Yang, Shun-Fa [5 ,9 ]
机构
[1] Taipei Med Univ, Grad Inst Clin Med, Coll Med, Taipei 110, Taiwan
[2] Taipei Med Univ, Wan Fang Hosp, Dept Med Educ & Res, Taipei 116, Taiwan
[3] Taipei Med Univ, Wan Fang Hosp, Div Hematol & Med Oncol, Dept Internal Med, Taipei 116, Taiwan
[4] Taipei Med Univ, Sch Med, Dept Urol, Taipei 110, Taiwan
[5] Chung Shan Med Univ, Inst Med, Taichung 402, Taiwan
[6] Taipei Med Univ, Wan Fang Hosp, Dept Urol, Taipei 116, Taiwan
[7] Chung Shan Med Univ, Sch Med, Taichung 402, Taiwan
[8] Chung Shan Med Univ Hosp, Dept Internal Med, Taichung 402, Taiwan
[9] Chung Shan Med Univ Hosp, Dept Med Res, Taichung 402, Taiwan
关键词
tricetin; apoptosis; c-Jun N-terminal kinase; reactive oxygen species; acute myeloid leukemia; ACUTE MYELOID-LEUKEMIA; RESISTANCE PROTEIN BCRP/ABCG2; CANCER CELLS; MITOCHONDRIAL PATHWAY; ARSENIC TRIOXIDE; DRUG-RESISTANCE; DEATH; SUPPRESSES; INDUCTION; GROWTH;
D O I
10.3390/ijms18081667
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML.
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页数:14
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