Jovanović Mirna, Podolski-Renić Ana, Krasavin Mikhail, Pešić Milica
Department of Neurobiology, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Organic Chemistry Division, Institute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russia.
Front Mol Biosci. 2022 May 19;9:883297. doi: 10.3389/fmolb.2022.883297. eCollection 2022.
The intracellular redox homeostasis is a dynamic balancing system between the levels of free radical species and antioxidant enzymes and small molecules at the core of cellular defense mechanisms. The thioredoxin (Trx) system is an important detoxification system regulating the redox milieu. This system is one of the key regulators of cells' proliferative potential as well, through the reduction of key proteins. Increased oxidative stress characterizes highly proliferative, metabolically hyperactive cancer cells, which are forced to mobilize antioxidant enzymes to balance the increase in free radical concentration and prevent irreversible damage and cell death. Components of the Trx system are involved in high-rate proliferation and activation of pro-survival mechanisms in cancer cells, particularly those facing increased oxidative stress. This review addresses the importance of the targetable redox-regulating Trx system in tumor progression, as well as in detoxification and protection of cancer cells from oxidative stress and drug-induced cytotoxicity. It also discusses the cancer cells' counteracting mechanisms to the Trx system inhibition and presents several inhibitors of the Trx system as prospective candidates for cytostatics' adjuvants. This manuscript further emphasizes the importance of developing novel multitarget therapies encompassing the Trx system inhibition to overcome cancer treatment limitations.
细胞内氧化还原稳态是细胞防御机制核心的自由基种类与抗氧化酶及小分子水平之间的动态平衡系统。硫氧还蛋白（Trx）系统是调节氧化还原环境的重要解毒系统。该系统也是细胞增殖潜能的关键调节因子之一，通过还原关键蛋白发挥作用。氧化应激增加是高度增殖、代谢活跃的癌细胞的特征，这些癌细胞被迫调动抗氧化酶来平衡自由基浓度的增加，防止不可逆转的损伤和细胞死亡。Trx系统的组成部分参与癌细胞的高速增殖和促生存机制的激活，尤其是那些面临氧化应激增加的癌细胞。本综述阐述了可靶向的氧化还原调节Trx系统在肿瘤进展以及癌细胞解毒、免受氧化应激和药物诱导的细胞毒性方面的重要性。还讨论了癌细胞对Trx系统抑制的对抗机制，并介绍了几种Trx系统抑制剂作为细胞抑制剂佐剂的潜在候选药物。本文进一步强调了开发包含Trx系统抑制的新型多靶点疗法以克服癌症治疗局限性的重要性。
