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Int. J. Mol. Sci. 2017, 18(8), 1667; doi:10.3390/ijms18081667

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

1
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
3
Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
4
Department of Urology, School of Medicine, Taipei Medical University, Taipei 110, Taiwan
5
Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
6
Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
7
School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
8
Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
9
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 24 May 2017 / Revised: 20 July 2017 / Accepted: 25 July 2017 / Published: 31 July 2017
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Abstract

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. View Full-Text
Keywords: tricetin; apoptosis; c-Jun N-terminal kinase; reactive oxygen species; acute myeloid leukemia tricetin; apoptosis; c-Jun N-terminal kinase; reactive oxygen species; acute myeloid leukemia
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MDPI and ACS Style

Chien, M.-H.; Chow, J.-M.; Lee, W.-J.; Chen, H.-Y.; Tan, P.; Wen, Y.-C.; Lin, Y.-W.; Hsiao, P.-C.; Yang, S.-F. Tricetin Induces Apoptosis of Human Leukemic HL-60 Cells through a Reactive Oxygen Species-Mediated c-Jun N-Terminal Kinase Activation Pathway. Int. J. Mol. Sci. 2017, 18, 1667.

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