Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia

Abstract

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 de- IntroductionAdvances in molecular pathogenesis have facilitated the development of therapeutic strategies targeted to molecular events critical for human malignancies. This is represented by the treatment of chronic myeloid leukemia (CML) with imatinib mesylate (STI571), a specifically designed inhibitor that targets the tyrosine kinase activity of the BCR-ABL protein and consequently induces apoptosis in vitro as well as in vivo in CML cells. [1][2][3][4][5][6] Recent clinical trials in the chronic phase of CML have also demonstrated the remarkable efficacy of this molecularly targeted agent to patients with CML. 7 However, a significant proportion of the treated patients with previously failed experiences of interferon therapy remained predominantly BCR-ABL ϩ , suggesting a risk of later relapse. 8 Furthermore, patients in the accelerated and blast-crisis phase revealed a high frequency of relapse or resistance to imatinib mesylate. 9-11 As a result, much interest is now focused on the development of combination therapies to improve response rates and prevent resistance or relapse. 12 Arsenic, the oldest and also the newest form of antileukemia drug, may promote apoptosis and exert anti-CML effects. 13 A treatment strategy that combines arsenic compounds that lower BCR-ABL levels, with imatinib mesylate that inhibits BCR-ABL tyrosine kinase activity, has indeed shown promising potential in inducing more apoptosis in BCR-ABL ϩ cells. [14][15][16] Clinical applications of similar strategies may potentially strengthen the curative effects of imatinib mesylate. To better evaluate additive or synergistic effects of the combination of ATO with imatinib mesylate in CML cells, and to develop more sophisticated clinical protocols, we treated the CML cell line K562 with ATO, imatinib...

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Some studies also suggested that ER stress could be involved in the anticancer action of arsenic trioxide (Du et al. 2006; Chen et al. 2012; Chiu et al.…”

Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4

“…ATO is used to be a therapeutic agent for acute promyelocytic leukemia (16). ATO also provokes ER stress that leads to downregulation of calcium signaling resulting in apoptosis (17). SP600125 is widely known as a reversible ATP competitive inhibitor of c-Jun N-terminal kinase (JNK).…”

A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia

“…Real-time RT-PCR analysis of BCR/ABL transcripts was performed as previously described (5,7). All experiments were performed 4 times, and the 2-sided paired t test was used for statistical analysis.…”

“…Arsenic compounds such as arsenic trioxide (As 2 O 3 ) and arsenic sulfide (As 4 S 4 , AS) have been used in the treatment of CML before the era of modern chemotherapy and more recently have been shown to be effective, particularly in combination with all-trans retinoic acid, in the treatment of acute promyelocytic leukemia (APL) (4). Indeed, some previous studies have reported the potentiating effects of As 2 O 3 when used in combination with IM in CML cells (5,6). A combination of AS and IM also induced apoptosis in CML cells (7) and the fact that AS can be used orally in humans as a relatively safe agent (8) makes it potentially a more appropriate partner for IM in anti-CML therapy.…”