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

Frontiers in molecular biosciences (2020-11-03)
Mirna Jovanović, Miodrag Dragoj, Daniil Zhukovsky, Dmitry Dar'in, Mikhail Krasavin, Milica Pešić, Ana Podolski-Renić
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Sigma-Aldrich
Dihydrorhodamine 123, ≥95%
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Thiazolyl Blue Tetrazolium Bromide, 98%
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Minimum Essential Medium Eagle, With Earle′s salts and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Paclitaxel, from Taxus yannanensis, powder
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Temozolomide, ≥98% (HPLC)
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Rhodamine 123, mitochondrial specific fluorescent dye
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Rhodamine 123, BioReagent, for fluorescence, ≥85% (HPLC)
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Fetal Bovine Serum, Research Grade, non-USA origin, sterile-filtered, suitable for cell culture