Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein.
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 (As(4)S(4)). Analysis of cell proliferation and clonogenic ability showed that As(4)S(4) 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 As(4)S(4) induced G(2)/M arrest whereas imatinib induced G(1) 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 As(4)S(4) 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 As(4)S(4) combination on CML.
Yin
Tong
T
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Second Medical University, 197 Ruijin Rd II, Shanghai 200025, China.
Wu
Ying-Li
YL
Sun
Hui-Ping
HP
Sun
Guan-Lin
GL
Du
Yan-Zhi
YZ
Wang
Kan-Kan
KK
Zhang
Ji
J
Chen
Guo-Qiang
GQ
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D000970:Antineoplastic Agents / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010879:Piperazines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D013440:Sulfides / Q000633:toxicity*
D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D004273:DNA, Neoplasm; D010879:Piperazines; D011743:Pyrimidines; D013440:Sulfides; C045816:arsenic trisulfide; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl