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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4219-4225.
Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-04-1433.
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Submitted April 15, 2004
Accepted July 26, 2004
Combined Effects of As4S4 and Imatinib on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein
Tong Yin, Ying-Li Wu, Hui-Ping Sun, Guan-Lin Sun, Yan-Zhi Du, Kan-Kan Wang, Ji Zhang, Guo-Qiang Chen, Sai-Juan Chen, and Zhu Chen*
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University(SSMU), Shanghai, China; Department of Medical Laboratory Science, Ruijin Medical College of Shanghai Second Medical University, Shanghai, China
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University(SSMU), Shanghai, China; Department of Pathophysiology, SSMU, Shanghai, China
Department of Hematology, Ruijin Hospital, SSMU, Shanghai, China
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University(SSMU), Shanghai, China
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University(SSMU), Shanghai, China; Health Science Center, SIBS, CAS and SSMU, Shanghai, China
* Corresponding author; email: zchen{at}stn.sh.cn.
Imatinib is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with Imatinib and arsenic sulfide (As4S4). Analysis of cell proliferation and clonogenic ability showed that As4S4 and Imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34+ cells from the non-leukemia donors. Examination of cell cycles showed that As4S4 induced G2/M arrest while Imatinib induced G1 arrest. Using a number of parameters such as morphology, Annexin V/PI, mitochondrial transmembrane potential, caspase3 activity and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through mitochondrial pathway. The two drugs also exhibited synergistic effect in targeting BCR-ABL protein. While As4S4 triggered its degradation and Imatinib inhibited its tyrosine kinase activity, combined use of the two led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of Imatinib/As4S4 combination on CML.
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