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.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells and the most common type of leukemia in adults
We found that superoxide was overproduced in HL-60 AML cells during tricetin treatment, which initiated a signal leading to activation of Jun N-terminal kinase (JNK)-mediated apoptosis
Our study showed that tricetin can induce caspase-9-mediated cell death, but the effect of tricetin on the membrane potential (MMP) in AML cells will be investigated in our future work
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells and the most common type of leukemia in adults. Despite significant improvements being made in the past three decades in the understanding of leukemia pathogenesis, prognostic factors, drug treatment, and patient care procedures, the prognosis of AML is still not good enough, and estimated 5-year overall survival after a standard chemotherapy is only 38% [1,2]. Some plant-derived natural products have been used as alternative treatments for leukemias including AML because of their extensive biological activities and comparatively low toxicities [4,5]. Tricetin has garnered much attention in relation to its anticancer activities such as antiproliferative and antimetastatic activities in many solid tumor cell models including breast [7], liver [8], lung [9], bone [10], and brain [11] tumors. It is quite clear that tricetin can inhibit the growth or metastasis of various solid tumor cells, the precise impact of tricetin on nonsolid tumors is still unclear
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