Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways
Authors
Xin-xin Xiong
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Ju-mei Liu
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Xin-yao Qiu
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Feng Pan
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Shang-bin Yu
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Xiao-qian Chen
Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Aim:
To investigate the effects of piperlongumine (PL), an anticancer alkaloid from long pepper plants, on the primary myeloid leukemia cells from patients and the mechanisms of action.
Methods:
Human BM samples were obtained from 9 patients with acute or chronic myeloid leukemias and 2 patients with myelodysplastic syndrome (MDS). Bone marrow mononuclear cells (BMMNCs) were isolated and cultured. Cell viability was determined using MTT assay, and apoptosis was examined with PI staining or flow cytometry. ROS levels in the cells were determined using DCFH-DA staining and flow cytometry. Expression of apoptotic and autophagic signaling proteins was analyzed using Western blotting.
Results:
PL inhibited the viability of BMMNCs from the patients with myeloid leukemias (with IC50 less than 20 μmol/L), but not that of BMMNCs from a patient with MDS. Furthermore, PL (10 and 20 μmol/L) induced apoptosis of BMMNCs from the patients with myeloid leukemias in a dose-dependent manner. PL markedly increased ROS levels in BMMNCs from the patients with myeloid leukemias, whereas pretreatment with the antioxidant N-acetyl-L-cysteine abolished PL-induced ROS accumulation and effectively reduced PL-induced cytotoxicity. Moreover, PL markedly increased the expression of the apoptotic proteins (Bax, Bcl-2 and caspase-3) and autophagic proteins (Beclin-1 and LC3B), and phosphorylation of p38 and JNK in BMMNCs from the patients with myeloid leukemias, whereas pretreatment with the specific p38 inhibitor SB203580 or the specific JNK inhibitor SP600125 partially reversed PL-induced ROS production, apoptotic/autophagic signaling activation and cytotoxicity.
Conclusion:
Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways.
Keywords: piperlongumine, ayurvedic medicine, myeloid leukemia, myelodysplastic syndrome, apoptosis, autophagy, ROS, p38, JNK, N-acetyl-L-cysteine, SB203580, SP600125
Author Biography
Feng Pan, Department of Pathophysiology, School of Basic Medicine; Key Laboratory of Neurological Diseases, Ministry of Education; Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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