Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia.
A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce markedly more cell apoptosis than imatinib mesylate alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic/additive action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing map (CPP-SOM), and methods of protein biochemistry to study cell apoptosis induced by imatinib mesylate, ATO, and the combination of the 2 agents in the CML cell line K562. Numerous features with temporospatial relationships were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. Imatinib mesylate appears to induce mainly the intrinsic pathway of cell apoptosis, whereas ATO induces the endoplasmic reticulum (ER) stress-mediated pathway of cell apoptosis, and the combination of the 2 agents seems to more effectively induce the intrinsic, extrinsic, and ER stress-mediated pathways of cell apoptosis, which results in a more effective and efficient induction of programmed cell death in K562 cells. This finding appears to be supported also by data derived from bone marrow cells of 2 patients with CML, one in chronic phase and the other in blast-crisis phase of the disease.
Du
Yanzhi
Y
State Key Laboratory of Medical Genomics and Shanghai Institute of Ruijin Hospital, School of Medicine of Shanghai Jiao Tong University, Shanghai 200025, China.
Wang
Kankan
K
Fang
Hai
H
Li
Junmin
J
Xiao
Dakai
D
Zheng
Peizheng
P
Chen
Yulong
Y
Fan
Huiyong
H
Pan
Xiaoling
X
Zhao
Chunjun
C
Zhang
Qinghua
Q
Imbeaud
Sandrine
S
Graudens
Esther
E
Eveno
Eric
E
Auffray
Charles
C
Chen
Saijuan
S
Chen
Zhu
Z
Zhang
Ji
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001549:Benzamides; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D010087:Oxides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D006131:Growth Inhibitors; D010087:Oxides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000077237:Arsenic Trioxide