Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy.
Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy.
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新型TrxR1抑制剂通过抑制胶质瘤细胞的侵袭和使胶质瘤细胞对化疗敏感而显示出治疗胶质瘤的潜力。
DOI：
10.3389/fmolb.2020.586146
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发表时间：
2020
影响因子：
5
通讯作者：
Podolski-Renić A
中科院分区：
文献类型：
--
作者：
Jovanović M;Dragoj M;Zhukovsky D;Dar'in D;Krasavin M;Pešić M;Podolski-Renić A
目前，可用的胶质母细胞瘤（GBM）治疗仍然无效，初始反应后复发，GBM患者的生存率低。GBM治疗能力有限的原因是高肿瘤异质性、侵袭性和耐药性的发生。因此，开发新的治疗策略至关重要。硫氧还蛋白还原酶（TrxR）是一种新的，有前途的目标，由于其在许多癌症类型中的过度表达和在癌症进展中的重要作用。先前对TrxR的Ugi型Michael受体-抑制剂的研究显示出理想的抗癌特性，对癌细胞具有显著的选择性。在此，两种TrxR抑制剂5和6在多药耐药（MDR）胶质瘤细胞系上进行了深入研究。除了抗氧化作用，5和6诱导细胞死亡，降低细胞增殖，并抑制胶质瘤细胞的侵袭和迁移。这两种化合物与替莫唑胺（TMZ）（GBM治疗的一线化疗药物）联合使用时显示出协同作用。此外，5和6影响可在癌细胞和血脑屏障（BBB）中发现的P-糖蛋白挤出泵的活性，因此显示出抑制癌细胞中的MDR表型和逃避BBB的潜力。总之，研究的TrxR抑制剂是有效的抗癌化合物，通过抑制硫氧还蛋白系统和干扰胶质瘤细胞的抗氧化防御系统发挥作用。它们适合与其他化疗药物联合使用，能够超越血脑屏障，克服MDR。因此，我们的研究结果表明进一步探索Ugi型Michael受体-TrxR抑制剂作为GBM治疗的辅助疗法的潜力。
Currently, available glioblastoma (GBM) treatment remains ineffective, with relapse after initial response and low survival rate of GBM patients. The reasons behind limited capacities for GBM treatment are high tumor heterogeneity, invasiveness, and occurrence of drug resistance. Therefore, developing novel therapeutic strategies is of utmost importance. Thioredoxin reductase (TrxR) is a novel, promising target due to its overexpression in many cancer types and important role in cancer progression. Previous research on Ugi-type Michael acceptors–inhibitors of TrxR showed desirable anticancer properties, with significant selectivity toward cancer cells. Herein, two TrxR inhibitors, 5 and 6, underwent in-depth study on multidrug-resistant (MDR) glioma cell lines. Besides the antioxidative effects, 5 and 6 induced cell death, decreased cell proliferation, and suppressed invasion and migration of glioma cells. Both compounds showed a synergistic effect in combination with temozolomide (TMZ), a first-line chemotherapeutic for GBM treatment. Moreover, 5 and 6 affected activity of P-glycoprotein extrusion pump that could be found in cancer cells and in the blood–brain barrier (BBB), thus showing potential for suppressing MDR phenotype in cancer cells and evading BBB. In conclusion, investigated TrxR inhibitors are effective anticancer compounds, acting through inhibition of the thioredoxin system and perturbation of antioxidative defense systems of glioma cells. They are suitable for combining with other chemotherapeutics, able to surpass the BBB and overcome MDR. Thus, our findings suggest further exploration of Ugi-type Michael acceptors–TrxR inhibitors’ potential as an adjuvant therapy for GBM treatment.
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乳腺癌细胞入侵和迁移中的硫氧还蛋白系统。
影响因子：
11.4
作者：
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影响因子：
7.4
作者：
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通讯作者：
Prieto, J