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

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Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy. / Jovanović, Mirna; Dragoj, Miodrag; Zhukovsky, Daniil ; Dar’in, Dmitry ; Krasavin, Mikhail; Pešić, Milica; Podolski-Renić, Ana.

In: Frontiers in Molecular Biosciences, Vol. 7, 586146, 06.10.2020.

Research output: Contribution to journal › Article › peer-review

BibTeX

@article{f1b37a5d8c3042738d5c69e863f55fc5,

title = "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{\textquoteright} potential as an adjuvant therapy for GBM treatment.",

keywords = "glioma, multidrug resistance, thioredoxin reductase 1, oxidative stress, temozolomide, invasion, THIOREDOXIN REDUCTASE, MAMMALIAN THIOREDOXIN, OXIDATIVE STRESS, DRUG-RESISTANCE, COLLATERAL SENSITIVITY, GLIOBLASTOMA CELLS, GENE-EXPRESSION, NITRIC-OXIDE, GLUTATHIONE, SYSTEM",

author = "Mirna Jovanovi{\'c} and Miodrag Dragoj and Daniil Zhukovsky and Dmitry Dar{\textquoteright}in and Mikhail Krasavin and Milica Pe{\v s}i{\'c} and Ana Podolski-Reni{\'c}",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Jovanovi{\'c}, Dragoj, Zhukovsky, Dar{\textquoteright}in, Krasavin, Pe{\v s}i{\'c} and Podolski-Reni{\'c}.",

year = "2020",

month = oct,

day = "6",

doi = "10.3389/fmolb.2020.586146",

language = "English",

volume = "7",

journal = "Frontiers in Molecular Biosciences",

issn = "2296-889X",

publisher = "Frontiers Media S.A.",

}

RIS

TY - JOUR

T1 - Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy

AU - Jovanović, Mirna

AU - Dragoj, Miodrag

AU - Zhukovsky, Daniil

AU - Dar’in, Dmitry

AU - Krasavin, Mikhail

AU - Pešić, Milica

AU - Podolski-Renić, Ana

PY - 2020/10/6

Y1 - 2020/10/6

N2 - 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.

AB - 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.

KW - glioma

KW - multidrug resistance

KW - thioredoxin reductase 1

KW - oxidative stress

KW - temozolomide

KW - invasion

KW - THIOREDOXIN REDUCTASE

KW - MAMMALIAN THIOREDOXIN

KW - OXIDATIVE STRESS

KW - DRUG-RESISTANCE

KW - COLLATERAL SENSITIVITY

KW - GLIOBLASTOMA CELLS

KW - GENE-EXPRESSION

KW - NITRIC-OXIDE

KW - GLUTATHIONE

KW - SYSTEM

UR - http://www.scopus.com/inward/record.url?scp=85093518423&partnerID=8YFLogxK

U2 - 10.3389/fmolb.2020.586146

DO - 10.3389/fmolb.2020.586146

M3 - Article

AN - SCOPUS:85093518423

VL - 7

JO - Frontiers in Molecular Biosciences

JF - Frontiers in Molecular Biosciences

SN - 2296-889X

M1 - 586146

ER -

ID: 70400229