Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary...

Reprograming of energy metabolism is a major hallmark of cancer, but its effective intervention is still a challenging task due to metabolic heterogeneity and plasticity of cancer cells. Herein, we report a general redox-based strategy for meeting the challenge. The strategy was exemplified by a dietary curcumin analogue (MitoCur-1) that was designed to target mitochondria (MitoCur-1). By virtue of its electrophilic and mitochondrial-targeting properties, MitoCur-1 generated reactive oxygen species (ROS) more effectively and selectively in HepG2 cells than in L02 cells via the inhibition of mitochondrial antioxidative thioredoxin reductase 2 (TrxR2). The ROS generation preferentially mediated the energy crisis of HepG2 cells in a dual-inhibition fashion against both mitochondrial and glycolytic metabolisms, which could hit the metabolic plasticity of HepG2 cells. The ROS-dependent energy crisis also allowed its preferential killing of HepG2 cells (IC₅₀ = 1.4 μM) over L02 cells (IC₅₀ = 9.1 μM), via induction of cell-cycle arrest, apoptosis and autophagic death, and its high antitumor efficacy in vivo, in nude mice bearing HepG2 tumors (15 mg/kg). These results highlight that inhibiting mitochondrial TrxR2 to produce ROS by electrophiles is a promising redox-based strategy for the effective intervention of cancer cell energy metabolic reprograming.