Seitz Rebecca, Tümen Deniz, Kunst Claudia, Heumann Phillip, Schmid Stephan, Kandulski Arne, Müller Martina, Gülow Karsten
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany.
Antioxidants (Basel). 2024 Sep 4;13(9):1078. doi: 10.3390/antiox13091078.
Cells constantly face the challenge of managing oxidants. In aerobic organisms, oxygen (O) is used for energy production, generating reactive oxygen species (ROS) as byproducts of enzymatic reactions. To protect against oxidative damage, cells possess an intricate system of redox scavengers and antioxidant enzymes, collectively forming the antioxidant defense system. This system maintains the redox equilibrium and enables the generation of localized oxidative signals that regulate essential cellular functions. One key component of this defense is the thioredoxin (Trx) system, which includes Trx, thioredoxin reductase (TrxR), and NADPH. The Trx system reverses oxidation of macromolecules and indirectly neutralizes ROS via peroxiredoxin (Prx). This dual function protects cells from damage accumulation and supports physiological cell signaling. However, the Trx system also shields tumors from oxidative damage, aiding their survival. Due to elevated ROS levels from their metabolism, tumors often rely on the Trx system. In addition, the Trx system regulates critical pathways such as proliferation and neoangiogenesis, which tumors exploit to enhance growth and optimize nutrient and oxygen supply. Consequently, the Trx system is a potential target for cancer therapy. The challenge lies in selectively targeting malignant cells without disrupting the redox equilibrium in healthy cells. The aim of this review article is threefold: first, to elucidate the function of the Trx system; second, to discuss the Trx system as a potential target for cancer therapies; and third, to present the possibilities for inhibiting key components of the Trx system, along with an overview of the latest clinical studies on these inhibitors.
细胞始终面临着管理氧化剂的挑战。在需氧生物中，氧气（O₂）用于产生能量，作为酶促反应的副产物产生活性氧（ROS）。为了防止氧化损伤，细胞拥有一个复杂的氧化还原清除剂和抗氧化酶系统，共同构成抗氧化防御系统。该系统维持氧化还原平衡，并能产生调节基本细胞功能的局部氧化信号。这种防御的一个关键组成部分是硫氧还蛋白（Trx）系统，它包括硫氧还蛋白、硫氧还蛋白还原酶（TrxR）和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）。Trx系统逆转大分子的氧化，并通过过氧化物酶（Prx）间接中和ROS。这种双重功能保护细胞免受损伤积累，并支持生理细胞信号传导。然而，Trx系统也能保护肿瘤免受氧化损伤，帮助它们存活。由于肿瘤代谢产生的ROS水平升高，肿瘤常常依赖Trx系统。此外，Trx系统调节增殖和新血管生成等关键途径，肿瘤利用这些途径来促进生长并优化营养和氧气供应。因此，Trx系统是癌症治疗的一个潜在靶点。挑战在于选择性地靶向恶性细胞而不破坏健康细胞中的氧化还原平衡。这篇综述文章的目的有三个：第一，阐明Trx系统的功能；第二，讨论Trx系统作为癌症治疗潜在靶点的情况；第三，介绍抑制Trx系统关键成分的可能性，以及对这些抑制剂的最新临床研究概述。
