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

Abstract

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.