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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 9; pp. 3378 - 3383
• Main Authors: Zhang, Qun-Ye, Mao, Jian-Hua, Liu, Ping, Huang, Qiu-Hua, Lu, Jing, Xie, Yin-Yin, Weng, Lin, Zhang, Yan, Chen, Quan, Chen, Sai-Juan, Chen, Zhu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.03.2009; National Acad Sciences
• Subjects: Animals; Antibodies; Apoptosis; Arsenic; Arsenic compounds; Arsenicals - therapeutic use; Benzamides; Biological Sciences; Cell cycle; Cell Line, Tumor; Chemical compounds; Chemotherapy; Chronic myeloid leukemia; Disease Models, Animal; Drug Synergism; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - metabolism; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Imatinib Mesylate; K562 cells; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Mice; Models, Molecular; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Piperazines - therapeutic use; Proteasome Endopeptidase Complex - metabolism; Protein Kinases - metabolism; Protein Structure, Tertiary; Proteins; Proteomes; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - therapeutic use; Signal Transduction; Sulfides - therapeutic use; Survival Rate; Systems Biology; TOR Serine-Threonine Kinases; Transcriptomes; Ubiquitins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0813142106

In this study, we show that combined use of Imatinib (IM) and arsenic sulfide [As₄S₄ (AS)] exerts more profound therapeutic effects in a BCR/ABL-positive mouse model of chronic myeloid leukemia (CML) than either drug as a single agent. A systematic analysis of dynamic changes of the proteome, phosphoproteome, and transcriptome in K562 cells after AS and/or IM treatment was performed to address the mechanisms underlying this synergy. Our data indicate that AS promotes the activities of the unfolded protein reaction (UPR) and ubiquitination pathway, which could form the biochemical basis for the pharmacological effects of this compound. In this CML model, AS targets BCR/ABL through the ubiquitination of key lysine residues, leading to its proteasomal degradation, whereas IM inhibits the PI3K/AKT/mTOR pathway. Combination of the 2 agents synergistically arrests the cell cycle, decreases activity of BCR/ABL, and leads to activation of intrinsic and extrinsic apoptosis pathways through complex modifications to both transcription and protein levels. Thus, these results suggest potential clinical benefits of IM/AS combination therapy for human CML.