Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives

Stanković, Tijana; Dankó, Balázs; Martins, Ana; Dragoj, Miodrag; Stojković, Sonja; Isaković, Aleksandra; Wang, Hui‐Chun; Wu, Yang Chang; Hunyadi, Attila; Pešić, Milica

doi:10.1007/s00280-015-2821-9

Cited by 19 publications

(16 citation statements)

References 35 publications

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“…6A , the total antioxidative capacities of all the tested drug-resistant cell types were lower than their corresponding wild types, which resulted in the accumulation of H 2 O 2 and the much higher oxidative stress in drug-resistant cells than the wild cell types. The lower antioxidative capacity of multidrug-resistant cancer cells has also been reported in a few papers 37 . This result can explain the selective cytotoxicity of spermine and spermidine to drug-resistant cells in media containing FBS.…”

Section: Resultsmentioning

confidence: 61%

Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells

Wang

Liu

et al. 2018

Sci Rep

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Serum is a common supplement for cell culture due to it containing the essential active components for the growth and maintenance of cells. However, the knowledges of the active components in serum are incomplete. Apart from the direct influence of serum components on cultured cells, the reaction of serum components with tested drugs cannot be ignored, which usually results in the false conclusion on the activity of the tested drugs. Here we report the toxicity effect of polyamines (spermidine and spermine) on cultured cells, especially on drug-resistant cancer cell lines, which resulted from the oxidative degradation of polyamines by amine oxidases in serum supplement. Upon adding spermidine or spermine, high concentration of H2O2, an enzyme oxidation product of polyamines, was generated in culture media containing ruminant serum, such as fetal bovine serum (FBS), calf serum, bovine serum, goat serum or horse serum, but not in the media containing human serum. Drug-resistant cancer cell lines showed much higher sensitivity to the oxidation products of polyamines (H2O2 and acrolein) than their wild cell lines, which was due to their low antioxidative capacity.

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Section: Resultsmentioning

confidence: 61%

Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells

Wang

Liu

et al. 2018

Sci Rep

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“…[15] Furthermore, protoapigenone and its 1´-O-butyl-and propargylether, the β-naphthoflavone analog WYC0209, 6-methylprotoflavone and 6-bromoprotoflavone showed selective cytotoxicity against certain MDR cancer cell lines, such as NCI-H460 human non-small cell lung carcinoma cells adapted to doxorubicin, U87 human glioma and DLD1 human colorectal cells, both adapted to paclitaxel. [16] On the other hand, cross-resistance (CR) to protoflavones was observed in C6 rat glioma cells adapted to carmustine, and CS/CR pattern appeared to be in line with altered antioxidative capacity of the MDR cells as compared to their parental cell lines. [16] Based on these results our aim was to systematically explore the cytotoxicity and antitumor potential of further protoflavone derivatives.…”

Section: Introductionmentioning

confidence: 97%

“…[16] On the other hand, cross-resistance (CR) to protoflavones was observed in C6 rat glioma cells adapted to carmustine, and CS/CR pattern appeared to be in line with altered antioxidative capacity of the MDR cells as compared to their parental cell lines. [16] Based on these results our aim was to systematically explore the cytotoxicity and antitumor potential of further protoflavone derivatives. In particular, we characterized the anticancer activity of a total of 52 compounds in a diverse panel of cancer cell lines including MDR derivatives expressing ABCB1 or ABCG2.…”

Section: Introductionmentioning

confidence: 97%

Synthesis and SAR Study of Anticancer Protoflavone Derivatives: Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters

et al. 2017

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There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7 and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux.

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“…After the initial analysis of cytotoxic activity and potential to induce RONS, we identified two leading compounds ( 5 and 6 ) for further exploration of their mechanisms of action. Since human and rat MDR glioma cell lines possess different antioxidative capacities ( Stankovic et al, 2015 ; Stojkovic et al, 2015 ), we aimed to compare their vulnerability to oxidative stress induced by TrxR1 inhibitors. Therefore, we further assessed their impact on the antioxidative defense system, mitochondrial membrane potential, cell death induction, and cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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

Jovanović

Dragoj

Zhukovsky

et al. 2020

Front. Mol. Biosci.

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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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Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives

Abstract: Our results suggest that MDR cancer cells can be more vulnerable to the pro-oxidative activity of protoflavones due to an impaired antioxidative defense that might arise during the adaptation processes provoked by chemotherapy.

Cited by 19 publications

References 35 publications

Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells

Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells

Synthesis and SAR Study of Anticancer Protoflavone Derivatives: Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters

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

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