Systems Understanding of Synergism Between As4S4 and Imatinib in Treating BCR/ABL Leukemia Model and in Attenuating BCR/ABL Oncoprotein as Well as Related Regulatory Networks

The combination of Imatinib and arsenic sulfide (As₄S₄) exerts more profound in vivo therapeutic effects on chronic myeloid leukemia (CML) at both organism and cellular levels, as evident for the first time in this paper by significantly prolonged lifespan in mouse leukemia model bearing BCR/ABL and induction of apoptosis of BCR/ABL expressing cells. To address mechanisms underlying this synergy, we performed systematic analysis of the dynamic change of proteome, phosphoproteome and transcriptome in K562 cells after As₄S₄ and/or Imatinib treatment with the support of principal component analysis (PCA) and self-organization maps (SOM). Moreover, protein biochemistry experiments were performed to confirm the important conclusions from multiomics study. The integrated information indicated that As₄S₄ promoted the unfolding protein reaction (UPR) and activity of ubiquitination pathway, which can be considered as a major biochemical basis of the pharmacological effects of this ancient medicine. In this context, As₄S₄ was shown to target BCR/ABL through ubiquitination of key lysine residues and led subsequently to its degradation by proteasome. Meanwhile, Imatinib inhibited the PI3K/AKT/mTOR pathway with synergism of As₄S₄ and arrested cell cycle. Combination of the two agents synergistically decreased activity and quantity of BCR/ABL and activated intrinsic and extrinsic apoptosis pathways. These complex multi-molecular target and multi-pathway modifications at protein level, together with those at transcriptional regulation level, ultimately resulted in the synergistic attenuation of BCR/ABL oncoprotein and the therapeutic effects on CML model.