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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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NEOPLASIA

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

From the State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, and the Department of Hematology, Ruijin Hospital, Shanghai Second Medical University (SSMU); the Department of Medical Laboratory Science, Ruijin Medical College of SSMU; the Department of Pathophysiology, SSMU; and the Health Science Center, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, and SSMU, Shanghai, China.

Imatinib (STI571, Gleevec) 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 nonleukemic donors. Examination of cell cycles showed that As4S4 induced G2/M arrest whereas imatinib induced G1 arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As4S4 triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As4S4 combination on CML.


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