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 more cell apoptosis than STI571 alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing maps (CPP-SOM) and methods of protein biochemistry to study proapoptotic and apoptotic activities in programmed cell death induced by STI571, ATO and the combination of the two agents in detail. Numerous features with temporospatial relationship were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. In consequence, STI571 induces the intrinsic pathway of cell apoptosis, whereas ATO induces the ER stress-mediated pathway of cell apoptosis, and the combination of the two agents induces 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 CML. The potential impact of this study on the development of more sophisticated therapy in human malignancy can be substantial.