Artesunate induces apoptosis through caspase-dependent and -independent mitochondrial pathways in human myelodysplastic syndrome SKM-1 cells.
Artesunate (ART) is a semi-synthetic derivative of artemisinin extracted from Artemisia annua (sweet wormwood) that is conventionally used in anti-malarial drugs and more recently in medications that induce tumor cell apoptosis. Here, we investigated the effects and mechanistic pathways of ART in human myelodysplastic syndrome (MDS), a condition that commonly progresses to acute myeloid leukemia (AML). Human MDS SKM-1 cells, primary bone marrow (PBM) mononuclear cells from patients with refractory anemia with excess blasts (RAEB) or MDS-AML (MDS cell group), and PBM stromal cells from three patients without hematological diseases (non-MDS cell group) were cultured for 24, 48, or 72 h with or without various ART concentrations. CCK-8, western blot, JC-1 fluorescence, and Annexin-V/Propidium iodide (PI) labeling were used to assess cell proliferation, protein levels, mitochondrial membrane potentials (MMPs) and apoptosis, respectively. ART administration dose- and time-dependently inhibited SKM-1 proliferation. At 24, 48, and 72 h, ART IC₅₀ values were 89.92, 4.24, and 1.28 μmol/L, respectively. ART only significantly inhibited proliferation in the MDS cell group, but it has little impact on proliferation of non-MDS cells. ART decreased MMPs, and dose-dependently induced SKM-1 cell apoptosis, peaking at 82.9% when treated with 200 μmol/L ART for 24h. Caspase-3 and -9 activation, poly(ADP-ribose) polymerase cleavage, decreased Bcl-2/Bax ratio and apoptosis inducing factor nuclear localization were implicated in apoptosis. Our results indicate that ART effectively induces apoptosis in SKM-1 cells through both caspase-dependent and -independent mitochondrial pathways.
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: yingwang321@163.com.
Ying
Y
Wang
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Jingci
J
Yang
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Li
L
Chen
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Jiamin
J
Wang
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Yaqian
Y
Wang
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Jianmin
J
Luo
Department of Hematology, West China Hospital, Sichuan University, 37, Guoxue Street, Wuhou District, Chengdu 640041, China.
Ling
L
Pan
Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: zhang_xuejun8@yahoo.com.cn.
Xuejun
X
Zhang
D017209:Apoptosis / Q000502:physiology; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D001562:Benzimidazoles / Q000032:analysis / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells; D002232:Carbocyanines / Q000032:analysis / Q000378:metabolism; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D012844:Sincalide / Q000032:analysis / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000378:metabolism
D037621:Artemisinins; D001562:Benzimidazoles; D002232:Carbocyanines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D000077332:Artesunate; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D012844:Sincalide
Apoptosis-inducing factor; Artesunate; Caspase-3; Caspase-9; Mitochondrial apoptosis pathways; Myelodysplastic syndrome