Dynamic and Temporal Transcriptomic Analysis Reveals Ferroptosis-Mediated Antileukemia Activity of S-DimethylarsinoGlutathione:Insights into Novel Therapeutic Strategy

S-dimethylarsino-glutathione(ZIO-101,darinaparsin®)exhibits broader antitumor activity and less toxicity than arsenic trioxide(ATO),a clinically used drug for acute promyelocytic leukemia(APL)treatment.However,the mechanisms of action underlying antileukemia activities of ZIO-101 remain largely unknown.Herein,by integrating dynamic transcriptomic analysis and biochemical characterizations,we for the first time delineated that ZIO-101 exerted antiproliferative effects against leukemia cells via activating ferroptosis pathway,a newly discovered iron-dependent programmed cell death,at the early stage,as evidenced by abnormally elevated intracellular iron contents and lipid peroxidation.We further demonstrated that silencing heme oxygenase 1(HMOX1),an important iron homeostasis-related gene,effectively attenuated ferroptosis induced by ZIO-101,with iron accumulation and lipid peroxidation being significantly alleviated.Significantly,we discovered that ZIO-101 and kinase inhibitors(Dasatinib/Dactolisib)could synergistically kill leukemia cells,with a combination index of<1.0 under all the tested drug concentrations.Our findings regarding the ferroptosis-mediated antileukemia activity of ZIO-101,based on the dynamic and temporal transcriptomic analysis,provide promising approaches to combat drug-resistant leukemia by combining ZIO-101 with kinase inhibitors.The methodology may be further exploited for uncovering the modes of action of other drugs.