Chmelyuk Nelly, Kordyukova Maria, Sorokina Maria, Sinyavskiy Semyon, Meshcheryakova Valeriya, Belousov Vsevolod, Abakumova Tatiana
Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
Laboratory of Biomedical nanomaterials, National Research Technological University "MISIS", Leninskiy Prospekt 4, 119049 Moscow, Russia.
Int J Mol Sci. 2025 Feb 27;26(5):2084. doi: 10.3390/ijms26052084.
Reactive oxygen species (ROS) play a key role in cancer progression and antitumor therapy. Glioblastoma is a highly heterogeneous tumor with different cell populations exhibiting various redox statuses. Elevated ROS levels in cancer cells promote tumor growth and simultaneously make them more sensitive to anticancer drugs, but further elevation leads to cell death and apoptosis. Meanwhile, various subsets of tumor cells, such a glioblastoma stem cells (GSC) or the cells in tumor microenvironment (TME), demonstrate adaptive mechanisms to excessive ROS production by developing effective antioxidant systems such as glutathione- and thioredoxin-dependent. GSCs demonstrate higher chemoresistance and lower ROS levels than other glioma cells, while TME cells create a pro-oxidative environment and have immunosuppressive effects. Both subpopulations have become an attractive target for developing therapies. Increased expression of thioredoxin reductase (TrxR) is often associated with tumor progression and poor patient survival. Various TrxR inhibitors have been investigated as potential anticancer therapies, including nitrosoureas, flavonoids and metallic complexes. Gold derivatives are irreversible inhibitors of TrxR. Among them, auranofin (AF), a selective TrxR inhibitor, has proven its effectiveness as a drug for the treatment of rheumatoid arthritis and its efficacy as an anticancer agent has been demonstrated in preclinical studies in vitro and in vivo. However, further clinical application of AF could be challenging due to the low solubility and insufficient delivery to glioblastoma. Different delivery strategies for hydrophobic drugs could be used to increase the concentration of AF in the brain. Combining different therapeutic approaches that affect the redox status of various glioma cell populations could become a new strategy for treating brain tumor diseases.
活性氧（ROS）在癌症进展和抗肿瘤治疗中起着关键作用。胶质母细胞瘤是一种高度异质性肿瘤，不同细胞群体表现出不同的氧化还原状态。癌细胞中ROS水平升高促进肿瘤生长，同时使它们对抗癌药物更敏感，但进一步升高会导致细胞死亡和凋亡。与此同时，肿瘤细胞的各种亚群，如胶质母细胞瘤干细胞（GSC）或肿瘤微环境（TME）中的细胞，通过发展有效的抗氧化系统，如谷胱甘肽和硫氧还蛋白依赖性系统，来展示对过量ROS产生的适应性机制。GSC比其他胶质瘤细胞表现出更高的化学抗性和更低的ROS水平，而TME细胞则创造了一个促氧化环境并具有免疫抑制作用。这两个亚群都已成为开发治疗方法的有吸引力的靶点。硫氧还蛋白还原酶（TrxR）表达增加通常与肿瘤进展和患者生存率低相关。各种TrxR抑制剂已作为潜在的抗癌疗法进行了研究，包括亚硝基脲、黄酮类化合物和金属配合物。金衍生物是TrxR的不可逆抑制剂。其中，金诺芬（AF）作为一种选择性TrxR抑制剂，已证明其作为治疗类风湿性关节炎药物的有效性，并且其作为抗癌剂的功效已在体外和体内的临床前研究中得到证实。然而，由于AF的低溶解度和向胶质母细胞瘤的递送不足，其进一步的临床应用可能具有挑战性。对于疏水性药物，可以采用不同的递送策略来增加AF在脑中的浓度。结合影响各种胶质瘤细胞群体氧化还原状态的不同治疗方法可能成为治疗脑肿瘤疾病的新策略。
