Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy

Abstract

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.

Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer

“…The observed changes in expression of the enzymes may indicate the expression required in individual cell lines to attempt to maintain an intracellular redox balance. In glioma cells, treatment with novel TrxR1 inhibitors increased mRNA expression of Trx and TrxR1 in response to high ROS levels [ 45 ]. In addition, an increase in the TrxR expression may be one of the reasons why luminal cells did not show as much increased radiosensitivity following IQ9 treatment.…”

Thioredoxin-dependent system. Application of inhibitors

“…This effect was noticed during a cell viability assay performed on human keratinocytes (HaCaT) 90,91 as well as neuroblastoma (SH-SY5Y) 90,91 and glioblastoma (U87 and U87-TxR) cell lines 92 . Despite the effective selective action of DVD-445 against cancer cells, it has been observed that neuroblastoma cells remain viable at approximately 80% [90][91][92] . In addition, some DVD-445 analogues also show inhibitory activity against TrxR activity, but not in cancer cells 90 .…”

“…The compound signed as DVD-445 deserves special attention because of its preferential effect on easily proliferating cancer cells 90 . This effect was noticed during a cell viability assay performed on human keratinocytes (HaCaT) 90 , 91 as well as neuroblastoma (SH-SY5Y) 90 , 91 and glioblastoma (U87 and U87-TxR) cell lines 92 . Despite the effective selective action of DVD-445 against cancer cells, it has been observed that neuroblastoma cells remain viable at approximately 80% 90–92 .…”

Circ-SMO-encoded 193 a.a. Confers Chemotherapy Resistance and Immune Escape to Glioma Stem Cells

“…To date, temozolomide is still the only adjuvant medicine. Spatial analysis indicated that the in the tumour is responsible for TMZ resistance [14]. Glioma stem cells play key roles in resistance to chemotherapy and radiotherapy [15].…”