EM23, A Natural Sesquiterpene Lactone from Elephantopus mollis, Induces Apoptosis in Human Myeloid Leukemia Cells through Thioredoxin- and Reactive Oxygen Species-Mediated Signaling Pathways.

Hongyu Li,Sheng Wang,Chao Xia,Fangyuan Shao,Wenbo Chen,Guangxiong Zhou,Manmei Li,Yaolan Li,Guocai Wang,Zhong Liu

doi:10.3389/fphar.2016.00077

Hongyu Li, Sheng Wang + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2016.00077

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Abstract

Elephantopus mollis (EM) is a traditional herbal medicine with multiple pharmacological activities. However, the efficacy of EM in treating human leukemia is currently unknown. In the current study, we report that EM23, a natural sesquiterpene lactone isolated from EM, inhibits the proliferation of human chronic myeloid leukemia (CML) K562 cells and acute myeloid leukemia (AML) HL-60 cells by inducing apoptosis. Translocation of membrane-associated phospholipid phosphatidylserines, changes in cell morphology, activation of caspases, and cleavage of PARP were concomitant with this inhibition. The involvement of the mitochondrial pathway in EM23-mediated apoptosis was suggested by observed disruptions in mitochondrial membrane potential. Mechanistic studies indicated that EM23 caused a marked increase in the level of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine, a ROS scavenger, almost fully reversed EM23-mediated apoptosis. In EM23-treated cells, the expression levels of thioredoxin (Trx) and thioredoxinreductase (TrxR), two components of the Trx system involved in maintaining cellular redox homeostasis, were significantly down-regulated. Concomitantly, Trx regulated the activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream regulatory targets, the p38, JNK, and ERK MAPKs. EM23-mediated activation of ASK1/MAPKs was significantly inhibited in the presence of NAC. Furthermore, tumor necrosis factor alpha (TNF-α)-mediated activation of nuclear factor-κB (NF-κB) was suppressed by EM23, as suggested by the observed blockage of p65 nuclear translocation, phosphorylation, and reversion of IκBα degradation following EM23 treatment. Taken together, these results provide important insights into the anticancer activities of the EM component EM23 against human CML K562 cells and AML HL-60 cells.

Highlights

Leukemia, a malignant disease affecting blood cells, usually begins in the bone marrow and is characterized by an aberrant accumulation of abnormal white blood cells
We investigated the anti-leukemia properties and associated molecular mechanisms of EM23, a natural sesquiterpene lactone isolated from Elephantopus mollis (EM), in the K562 and HL-60 human chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines
When the treatment time was extended to 72 h, EM23 showed more significant proliferation inhibitory activities, with IC50 values of 6.3 and 1.4 μM for K562 and HL-60 cells, respectively

Summary

Introduction

A malignant disease affecting blood cells, usually begins in the bone marrow and is characterized by an aberrant accumulation of abnormal white blood cells. Chemotherapy remains one of the major therapeutic approaches for leukemia. Both AML and CML are myeloid or myelogenous leukemias, and the initial cancerous changes associated with these cancers affect certain blood-forming cells in the bone marrow. Bone marrow transplantation/allogeneic stem cell transplantation is the only curative treatment for CML (Goldman et al, 2010). TKIs that target BCR-ABL are the standard treatment for CML. New second- and third- generation TKIs, such as dasatinib, nilotinib, and bosutinib, exhibit superior inhibitory activity against BCR-ABL compared to imatinib. TKIs are extensively used, serious drug-drug interactions and emerging resistance of CML cells to TKIs through multiple mechanisms has limited their clinical application (Volpe et al, 2009)

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