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Article ; Online: The Role of the Thioredoxin Detoxification System in Cancer Progression and Resistance

Mirna Jovanović / Ana Podolski-Renić / Mikhail Krasavin / Milica Pešić

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract: The intracellular redox homeostasis is a dynamic balancing system between the levels of free radical species and antioxidant enzymes and small molecules at the core of cellular defense mechanisms. The thioredoxin (Trx) system is an important ... ...

Abstract	The intracellular redox homeostasis is a dynamic balancing system between the levels of free radical species and antioxidant enzymes and small molecules at the core of cellular defense mechanisms. The thioredoxin (Trx) system is an important detoxification system regulating the redox milieu. This system is one of the key regulators of cells’ proliferative potential as well, through the reduction of key proteins. Increased oxidative stress characterizes highly proliferative, metabolically hyperactive cancer cells, which are forced to mobilize antioxidant enzymes to balance the increase in free radical concentration and prevent irreversible damage and cell death. Components of the Trx system are involved in high-rate proliferation and activation of pro-survival mechanisms in cancer cells, particularly those facing increased oxidative stress. This review addresses the importance of the targetable redox-regulating Trx system in tumor progression, as well as in detoxification and protection of cancer cells from oxidative stress and drug-induced cytotoxicity. It also discusses the cancer cells’ counteracting mechanisms to the Trx system inhibition and presents several inhibitors of the Trx system as prospective candidates for cytostatics’ adjuvants. This manuscript further emphasizes the importance of developing novel multitarget therapies encompassing the Trx system inhibition to overcome cancer treatment limitations.
Keywords	Trx ; TrxR ; RONS ; oxidative stress ; antioxidative defence ; resistance to therapy ; Biology (General) ; QH301-705.5
Subject code	500 ; 610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SELENIUM SUBSTITUTION – EFFECT ON THYROID FUNCTION

Milica Pešić / Danijela Radojković

Acta Medica Medianae, Vol 54, Iss 1, Pp 56-

2015 Volume 59

Abstract: The understanding of the essential role of selenium (Se) in thyroid hormone synthesis, metabolism and action, as well as normal thyroid function, increased during the past decades. The thyroid gland is among the human tissues with the highest Se content ... ...

Abstract	The understanding of the essential role of selenium (Se) in thyroid hormone synthesis, metabolism and action, as well as normal thyroid function, increased during the past decades. The thyroid gland is among the human tissues with the highest Se content per mas unit, similar to other endocrine organs and brain. Biological actions of Se are mediated, in most cases, through the expression of at least 30 selenoproteins coded by 25 selenoprotein genes in the human. Via the selenoproteins, selenium can influence the cell function through antioxidant activites, modifying redox status and thyroid hormone synthesis and metabolism. Selenoproteins iodothyronine deiodinases are present in most tissues and have a role to increase the production of bioactive tri-iodothyronine. Futhermore, Se has been shown to be important in the regulation of immune function. Se deficiency is accompained by the loss of immune competence. The links between Se deficiency, altered immune function and inflamation have prompted studies in humans to examine if Se suplementation can modify auto-antibodies production in patients with chronic autoimmune thyroiditis. Until now, several randomised prospective clinical trials have been performed in patients with established chronic autoimmune thyrioditis. The clinical endpoint of each study was the decrease in TPO antibodies concentration after 3-12 months of treatment. Ussualy, the dosage of daily Se supplementation was 200µg. Selenium suplemetation had no significant effect on the concentration of TSH or thyroid hormone concentrations. These studies indicate that Se treatment result in reduced inflammatory activity, but it does not cure chronc autoimmune process.
Keywords	thyroid gland ; trace element ; selenium ; Medicine ; R
Subject code	610
Language	English
Publishing date	2015-03-01T00:00:00Z
Publisher	University in Nis, Faculty of Medicine
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immunofluorescence-Based Assay for High-Throughput Analysis of Multidrug Resistance Markers in Non-Small Cell Lung Carcinoma Patient-Derived Cells

Jelena Dinić / Ana Podolski-Renić / Miodrag Dragoj / Sofija Jovanović Stojanov / Ana Stepanović / Ema Lupšić / Milica Pajović / Mirna Jovanović / Dušica Petrović Rodić / Dragana Marić / Maja Ercegovac / Milica Pešić

Diagnostics, Vol 13, Iss 24, p

2023 Volume 3617

Abstract: Lung cancer remains the leading cause of cancer death globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Multidrug resistance (MDR), often caused by ATP-binding cassette (ABC) transporters, represents a significant ... ...

Abstract	Lung cancer remains the leading cause of cancer death globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Multidrug resistance (MDR), often caused by ATP-binding cassette (ABC) transporters, represents a significant obstacle in the treatment of NSCLC. While genetic profiling has an important role in personalized therapy, functional assays that measure cellular responses to drugs are gaining in importance. We developed an automated microplate-based immunofluorescence assay for the evaluation of MDR markers ABCB1, ABCC1, and ABCG2 in cells obtained from NSCLC patients through high-content imaging and image analysis, as part of a functional diagnostic approach. This assay effectively discriminated cancer from non-cancer cells within mixed cultures, which is vital for accurate assessment of changes in MDR marker expression in different cell populations in response to anticancer drugs. Validation was performed using established drug-sensitive (NCI-H460) and drug-resistant (NCI-H460/R) NSCLC cell lines, demonstrating the assay’s capacity to distinguish and evaluate different MDR profiles. The obtained results revealed wide-ranging effects of various chemotherapeutic agents on MDR marker expression in different patient-derived NSCLC cultures, emphasizing the need for MDR diagnostics in NSCLC. In addition to being a valuable tool for assessing drug effects on MDR markers in different cell populations, the assay can complement genetic profiling to optimize treatment. Further assay adaptations may extend its application to other cancer types, improving treatment efficacy while minimizing the development of resistance.
Keywords	lung cancer ; NSCLC ; multidrug resistance ; MDR markers ; ABCB1 ; ABCC1 ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nano-Motion Analysis for Rapid and Label Free Assessing of Cancer Cell Sensitivity to Chemotherapeutics

Petar Stupar / Ana Podolski-Renić / Maria Ines Villalba / Miodrag Dragoj / Sofija Jovanović Stojanov / Milica Pešić / Sandor Kasas

Medicina, Vol 57, Iss 446, p

2021 Volume 446

Abstract: Background and Objectives : Optimization of chemotherapy is crucial for cancer patients. Timely and costly efficient treatments are emerging due to the increasing incidence of cancer worldwide. Here, we present a methodology of nano-motion analysis that ... ...

Abstract	Background and Objectives : Optimization of chemotherapy is crucial for cancer patients. Timely and costly efficient treatments are emerging due to the increasing incidence of cancer worldwide. Here, we present a methodology of nano-motion analysis that could be developed to serve as a screening tool able to determine the best chemotherapy option for a particular patient within hours. Materials and Methods : Three different human cancer cell lines and their multidrug resistant (MDR) counterparts were analyzed with an atomic force microscope (AFM) using tipless cantilevers to adhere the cells and monitor their nano-motions. Results : The cells exposed to doxorubicin (DOX) differentially responded due to their sensitivity to this chemotherapeutic. The death of sensitive cells corresponding to the drop in signal variance occurred in less than 2 h after DOX application, while MDR cells continued to move, even showing an increase in signal variance. Conclusions : Nano-motion sensing can be developed as a screening tool that will allow simple, inexpensive and quick testing of different chemotherapeutics for each cancer patient. Further investigations on patient-derived tumor cells should confirm the method’s applicability.
Keywords	atomic force microscope ; cantilever ; nano-motion ; cancer cells ; multidrug resistance ; personalized therapy ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Incidence trend of type 1 diabetes mellitus in Serbia.

Vojislav, Ciric / Natasa, Rancic / Milica, Pesic / Slobodan, Antic / Radivoj, Kocic / Danijela, Radojkovic / Sasa, Radenkovic

BMC endocrine disorders

2020 Volume 20, Issue 1, Page(s) 34

Abstract: Background: The incidence of type 1 diabetes mellitus (T1DM) increased worldwide. The objective of the paper was to compare the incidence trend of T1DM in children and adolescents aged 0-19 and in adults under 30 years of age in Serbia from 2006 to 2017. ...

Abstract	Background: The incidence of type 1 diabetes mellitus (T1DM) increased worldwide. The objective of the paper was to compare the incidence trend of T1DM in children and adolescents aged 0-19 and in adults under 30 years of age in Serbia from 2006 to 2017. Additional aim was to compare incidence rates of T1DM and type 2 diabetes mellitus (T2DM) among adults aged 20-24 and 25-29 years of age. Methods: Trends and annual percentage change (APC) of the incidence rate with corresponding 95% confidence intervals (CI) were calculated by Joinpoint Regression Analyses. Results: We found a significant increase of incidence in children aged 5-9 with the APC of 5.7% (95%CI: 2.3-9.1), and in children aged 10-14 with the APC of 2.1% (95%CI: 0.6-3.6). A significant decrease of incidence was determined in adolescents aged 15-19 with the APC -4.9% (95%CI: - 8.9 to - 0.7) and in adults aged 25-29 with the APC -7.3% (95%CI: - 12.5 to - 1.8). Conclusion: The increase of incidence in children aged 0-14 and its decrease after 15 years of age showed that T1DM is predominantly a metabolic disease of children in Serbia. A significant increase in incidence was recorded in two age groups, namely 5-9 and 10-14 years of age. The highest increase was in children aged 5-9 and the highest incidence rate was in children aged 10-14. An insignificant increasing of T2DM incidence was observed in young adults aged 25-29. The increase in incidence rates in children, but not in young adults, suggests that the precipitating factors of children-onset disease may differ from those of adult-onset T1DM.
MeSH term(s)	Adolescent ; Adult ; Age of Onset ; Child ; Child, Preschool ; Diabetes Mellitus, Type 1/epidemiology ; Female ; Follow-Up Studies ; Humans ; Incidence ; Infant ; Infant, Newborn ; Male ; Prognosis ; Serbia/epidemiology ; Young Adult
Language	English
Publishing date	2020-03-09
Publishing country	England
Document type	Journal Article
ISSN	1472-6823
ISSN (online)	1472-6823
DOI	10.1186/s12902-020-0504-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Interplay of Darwinian Selection, Lamarckian Induction and Microvesicle Transfer on Drug Resistance in Cancer

Arturo Álvarez-Arenas / Ana Podolski-Renic / Juan Belmonte-Beitia / Milica Pesic / Gabriel F. Calvo

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 13

Abstract: Abstract Development of drug resistance in cancer has major implications for patients’ outcome. It is related to processes involved in the decrease of drug efficacy, which are strongly influenced by intratumor heterogeneity and changes in the ... ...

Abstract	Abstract Development of drug resistance in cancer has major implications for patients’ outcome. It is related to processes involved in the decrease of drug efficacy, which are strongly influenced by intratumor heterogeneity and changes in the microenvironment. Heterogeneity arises, to a large extent, from genetic mutations analogously to Darwinian evolution, when selection of tumor cells results from the adaptation to the microenvironment, but could also emerge as a consequence of epigenetic mutations driven by stochastic events. An important exogenous source of alterations is the action of chemotherapeutic agents, which not only affects the signalling pathways but also the interactions among cells. In this work we provide experimental evidence from in vitro assays and put forward a mathematical kinetic transport model to describe the dynamics displayed by a system of non-small-cell lung carcinoma cells (NCI-H460) which, depending on the effect of a chemotherapeutic agent (doxorubicin), exhibits a complex interplay between Darwinian selection, Lamarckian induction and the nonlocal transfer of extracellular microvesicles. The role played by all of these processes to multidrug resistance in cancer is elucidated and quantified.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation

Gabrielle Bangay / Vera M. S. Isca / Daniel J. V. A. Dos Santos / Ricardo J. Ferreira / Salvatore Princiotto / Mirna Jovanovic / Milica Pesic / Patricia Rijo

Medical Sciences Forum, Vol 14, Iss 144, p

2022 Volume 144

Abstract: The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression of membrane transport proteins, such as P-glycoprotein (P- ... ...

Abstract	The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein kinases C (PKC) isoforms continues to be a major impediment to effective therapy. Known for their medicinal properties, species from Plectranthus have been reported to have cytotoxicity against various cancer cell lines due to diterpenes, such as 7α-acetoxy-6β-hydroxyroyleanone ( Roy ) and 6,7-dehydroroyleanone ( DeRoy ). Based on molecular docking simulations, 10 semi-synthetic derivatives of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was demonstrated that three abietane diterpenoids induced P-gp inhibition in MDR cancer cell lines. As regards the PKC activity, further analogues were tested as PKC (α, βI, δ, ε and ζ) modulators; one benzoylated derivative showed the ability to selectively activate PKC-δ, while the natural compound DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms. Further investigations are ongoing to prepare analogues of other biologically active diterpenoids to obtain potential hits as P-gp and PKC modulators.
Keywords	royleanones ; diterpenes ; P-gp ; PKC ; analogues ; cancer ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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

Mirna Jovanović / Miodrag Dragoj / Daniil Zhukovsky / Dmitry Dar’in / Mikhail Krasavin / Milica Pešić / Ana Podolski-Renić

Frontiers in Molecular Biosciences, Vol

2020 Volume 7

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 ... ...

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.
Keywords	glioma ; multidrug resistance ; thioredoxin reductase 1 ; oxidative stress ; temozolomide ; invasion ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells

Jelena Dinić / Ana Podolski-Renić / Mirna Jovanović / Loana Musso / Ivanka Tsakovska / Ilza Pajeva / Sabrina Dallavalle / Milica Pešić

International Journal of Molecular Sciences, Vol 20, Iss 18, p

2019 Volume 4575

Abstract: Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity ... ...

Abstract	Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure−activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.
Keywords	isoxazolonaphthoquinones ; Hsp90 inhibitors ; P-glycoprotein inhibitors ; cancer ; multidrug resistance ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Jatrophane diterpenoids with multidrug-resistance modulating activity from the latex of Euphorbia nicaeensis

Krstić, Gordana / Ivana S. Aljančić / Milica Pešić / Milka Jadranin / Nina M. Todorović / Tijana Stanković / Vele V. Tešević

Phytochemistry. 2018 Apr., v. 148

2018

Abstract: Seven previously undescribed jatrophane diterpenoids, nicaeenin A–G, with eight known jatrophane diterpenoids, namely euphodendrophanes A–C, F, N, O, Q, S, were isolated from latex of Euphorbia nicaeensis collected in Serbia. The chemical structures of ... ...

Abstract	Seven previously undescribed jatrophane diterpenoids, nicaeenin A–G, with eight known jatrophane diterpenoids, namely euphodendrophanes A–C, F, N, O, Q, S, were isolated from latex of Euphorbia nicaeensis collected in Serbia. The chemical structures of the compounds were determined by spectroscopic analysis including 1D and 2D NMR and HRESIMS experiments.All but one of the previously undescribed jatrophanes, showed significant potential to inhibit P-glycoprotein (P-gp) activity in two MDR cancer cells (NCI-H460/R and DLD1-TxR). The most powerful were nicaeenin F and nicaeenin G. Moreover nicaeenin G significantly stronger sensitized NCI-H460/R cells to DOX than Dex-VER.
Keywords	chemical structure ; diterpenoids ; Euphorbia ; latex ; multiple drug resistance ; neoplasm cells ; neoplasms ; nuclear magnetic resonance spectroscopy ; P-glycoproteins ; spectral analysis ; Serbia
Language	English
Dates of publication	2018-04
Size	p. 104-112.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	208884-8
ISSN	1873-3700 ; 0031-9422
ISSN (online)	1873-3700
ISSN	0031-9422
DOI	10.1016/j.phytochem.2018.01.016
Database	NAL-Catalogue (AGRICOLA)

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