Arsenic trioxide mediates intrinsic and extrinsic pathways of apoptosis and cell cycle arrest in acute megakaryocytic leukemia.
Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy. Acute megakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible. In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01. Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3. ATO activated the intrinsic (mitochondrial) pathway of apoptosis, which involved disrupting mitochondrial membrane potential, increased Bax/Bcl-2 ratio and caspase-9 activation, as well as the extrinsic (death receptor) pathway mediated by Fas and caspase-8 activation. We provided the first evidence that ATO stimulated expressions of CD137 mRNA and protein, which might be relevant to the extrinsic mechanism. ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific. The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.
Lam
Hubert Kin Bong
HK
Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong, P.R. China.
Li
Karen
K
Chik
Ki Wai
KW
Yang
Mo
M
Liu
Venus Chi Ting
VC
Li
Chi Kong
CK
Fok
Tai Fai
TF
Ng
Pak Cheung
PC
Shing
Matthew Ming Kong
MM
Chuen
Carmen Ka Yee
CK
Yuen
Patrick Man Pan
PM
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D001152:Arsenicals; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077237:Arsenic Trioxide