State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
School of Public Health, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
J Agric Food Chem. 2022 Mar 9;70(9):2898-2910. doi: 10.1021/acs.jafc.1c07690. Epub 2022 Feb 25.
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 (IC = 1.4 μM) over L02 cells (IC = 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.
能量代谢的重新编程是癌症的一个主要标志，但由于癌细胞的代谢异质性和可塑性，其有效干预仍然是一个具有挑战性的任务。在此，我们报告了一种基于氧化还原的通用策略来应对这一挑战。该策略的一个例子是一种饮食姜黄素类似物（MitoCur-1），它被设计用于靶向线粒体（MitoCur-1）。由于其亲电性和靶向线粒体的特性，MitoCur-1 通过抑制线粒体抗氧化硫氧还蛋白还原酶 2（TrxR2），在 HepG2 细胞中比在 L02 细胞中更有效地和选择性地产生活性氧（ROS）。ROS 的产生以双重抑制的方式优先介导 HepG2 细胞的能量危机，既抑制线粒体代谢又抑制糖酵解代谢，这可以打击 HepG2 细胞的代谢可塑性。ROS 依赖性的能量危机也允许其通过诱导细胞周期停滞、细胞凋亡和自噬死亡，优先杀死 HepG2 细胞（IC = 1.4 μM）而不是 L02 细胞（IC = 9.1 μM），并在携带 HepG2 肿瘤的裸鼠体内表现出高抗肿瘤功效（15 mg/kg）。这些结果强调，通过亲电物抑制线粒体 TrxR2 产生 ROS 是一种有前途的基于氧化还原的策略，可有效干预癌细胞能量代谢重编程。
