A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia.
In this study, we show that combined use of Imatinib (IM) and arsenic sulfide [As(4)S(4) (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.
Zhang
Qun-Ye
QY
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.
Mao
Jian-Hua
JH
Liu
Ping
P
Huang
Qiu-Hua
QH
Lu
Jing
J
Xie
Yin-Yin
YY
Weng
Lin
L
Zhang
Yan
Y
Chen
Quan
Q
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D000818:Animals; D001152:Arsenicals / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D015398:Signal Transduction; D013440:Sulfides / Q000627:therapeutic use*; D015996:Survival Rate; D049490:Systems Biology; D058570:TOR Serine-Threonine Kinases; D014452:Ubiquitins / Q000378:metabolism
D001152:Arsenicals; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D013440:Sulfides; D058570:TOR Serine-Threonine Kinases; D014452:Ubiquitins; C045816:arsenic trisulfide; C546842:MTOR protein, human; C546843:mTOR protein, mouse