Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 3 166 28 Prague 6 Czechia

Department of Medical Microbiology Albert Szent Györgyi Medical School University of Szeged Semmelweis utca 6 Szeged 6725 Hungary

Institute of Medical Biology Genetics and Clinical Genetics Faculty of Medicine Comenius University in Bratislava Sasinkova 4 811 08 Bratislava Slovakia

Instituto de Química Orgánica General Consejo Superior de Investigaciones Científicas Juan de la Cierva 3 28006 Madrid Spain

Laboratory of Pharmacogenomics Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 323 00 Pilsen Czechia

Toxicogenomics Unit National Institute of Public Health Šrobárova 49 100 00 Prague Czechia

Zobrazit více v PubMed

Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. PubMed DOI

Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 2020;21:3233. doi: 10.3390/ijms21093233. PubMed DOI PMC

Kathawala RJ, Gupta P, Ashby CR, Jr, Chen ZS. The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist. Updat. 2015;18:1–17. doi: 10.1016/j.drup.2014.11.002. PubMed DOI

Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum. Genom. 2009;3:281–290. doi: 10.1186/1479-7364-3-3-281. PubMed DOI PMC

Chen ZJ, et al. Association of ABCA2 expression with determinants of Alzheimer's disease. Faseb J. 2004;18:1129–1131. doi: 10.1096/fj.03-1490fje. PubMed DOI

Domenichini A, Adamska A, Falasca M. ABC transporters as cancer drivers: Potential functions in cancer development. Biochim. Biophys. Acta Gen. Subj. 1863;52–60:2019. doi: 10.1016/j.bbagen.2018.09.019. PubMed DOI

Kvackajová-Kisucká J, Barancík M, Breier A. Drug transporters and their role in multidrug resistance of neoplastic cells. Gen. Physiol. Biophys. 2001;20:215–237. PubMed

Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta. 1976;455:152–162. doi: 10.1016/0005-2736(76)90160-7. PubMed DOI

Fromm MF. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol. Sci. 2004;25:423–429. doi: 10.1016/j.tips.2004.06.002. PubMed DOI

Chambers C, et al. Defying multidrug resistance! Modulation of related transporters by flavonoids and flavonolignans. J. Agric. Food Chem. 2019 doi: 10.1021/acs.jafc.9b00694. PubMed DOI

Cole SP. Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. J. Biol. Chem. 2014;289:30880–30888. doi: 10.1074/jbc.R114.609248. PubMed DOI PMC

Peña-Solórzano D, Stark SA, König B, Sierra CA, Ochoa-Puentes C. ABCG2/BCRP: Specific and nonspecific modulators. Med. Res. Rev. 2017;37:987–1050. doi: 10.1002/med.21428. PubMed DOI

Gonzalez-Angulo, A. M., Morales-Vasquez, F. & Hortobagyi, G. N. Overview of resistance to systemic therapy in patients with breast cancer. In Breast Cancer Chemosensitivity (eds Dihua Yu & Mien-Chie Hung) 1–22 (Springer New York, 2007). PubMed

Bartolini D, et al. Selenocompounds in cancer therapy: An overview. Adv. Cancer Res. 2017;136:259–302. doi: 10.1016/bs.acr.2017.07.007. PubMed DOI

Freitas M, Alves V, Sarmento-Ribeiro AB, Mota-Pinto A. Combined effect of sodium selenite and docetaxel on PC3 metastatic prostate cancer cell line. Biochem. Biophys. Res. Commun. 2011;408:713–719. doi: 10.1016/j.bbrc.2011.04.109. PubMed DOI

Domínguez-Álvarez E, et al. Identification of selenocompounds with promising properties to reverse cancer multidrug resistance. Bioorg. Med. Chem. Lett. 2016;26:2821–2824. doi: 10.1016/j.bmcl.2016.04.064. PubMed DOI

Szemeredi N, et al. Cyano- and ketone-containing selenoesters as multi-target compounds against resistant cancers. Cancers. 2021 doi: 10.3390/cancers13184563. PubMed DOI PMC

Viktorova J, et al. Antioxidant, anti-inflammatory, and multidrug resistance modulation activity of silychristin derivatives. Antioxidants. 2019 doi: 10.3390/antiox8080303. PubMed DOI PMC

Daniel P, Halada P, Jelínek M, Balušíková K, Kovář J. Differentially expressed mitochondrial proteins in human MCF7 breast cancer cells resistant to paclitaxel. Int. J. Mol. Sci. 2019;20:2986. doi: 10.3390/ijms20122986. PubMed DOI PMC

Němcová-Fürstová V, et al. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. Toxicol. Appl. Pharmacol. 2016;310:215–228. doi: 10.1016/j.taap.2016.09.020. PubMed DOI

Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: Synthesis, identity, and their role in human health. Antioxid. Redox Signal. 2007;9:775–806. doi: 10.1089/ars.2007.1528. PubMed DOI

Fernandes AP, Gandin V. Selenium compounds as therapeutic agents in cancer. Biochim. Biophys. Acta. 1850;1642–1660:2015. doi: 10.1016/j.bbagen.2014.10.008. PubMed DOI

Gajdács M, et al. Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line. Bioorg. Med. Chem. Lett. 2017;27:797–802. doi: 10.1016/j.bmcl.2017.01.033. PubMed DOI

Csonka A, et al. Selenoesters and selenoanhydrides as novel agents against resistant breast cancer. Anticancer Res. 2019;39:3777–3783. doi: 10.21873/anticanres.13526. PubMed DOI

Pluchino KM, Hall MD, Goldsborough AS, Callaghan R, Gottesman MM. Collateral sensitivity as a strategy against cancer multidrug resistance. Drug Resist. Updat. 2012;15:98–105. doi: 10.1016/j.drup.2012.03.002. PubMed DOI PMC

Kunz PL, et al. Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors. Invest. New Drugs. 2012;30:2364–2370. doi: 10.1007/s10637-012-9800-3. PubMed DOI PMC

Kelly RJ, et al. A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. Oncologist. 2012;17:512. doi: 10.1634/theoncologist.2012-0080. PubMed DOI PMC

Zhang H, et al. In vitro, in vivo and ex vivo characterization of ibrutinib: A potent inhibitor of the efflux function of the transporter MRP1. Br. J. Pharmacol. 2014;171:5845–5857. doi: 10.1111/bph.12889. PubMed DOI PMC

Mollazadeh S, Sahebkar A, Hadizadeh F, Behravan J, Arabzadeh S. Structural and functional aspects of P-glycoprotein and its inhibitors. Life Sci. 2018;214:118–123. doi: 10.1016/j.lfs.2018.10.048. PubMed DOI

Leary M, Heerboth S, Lapinska K, Sarkar S. Sensitization of drug resistant cancer cells: A matter of combination therapy. Cancers (Basel). 2018 doi: 10.3390/cancers10120483. PubMed DOI PMC

Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis. 2021;12:339. doi: 10.1038/s41419-021-03614-x. PubMed DOI PMC

Zu Y, Yang Z, Tang S, Han Y, Ma J. Effects of P-glycoprotein and its inhibitors on apoptosis in K562 cells. Molecules. 2014;19:13061–13075. doi: 10.3390/molecules190913061. PubMed DOI PMC

Dludla, P. et al. The impact of dimethyl sulfoxide on oxidative stress and cytotoxicity in various experimental models. Toxicology. (eds Patel, V. B. & Preedy, V. R.) 243–261 (Academic Press, 2020). 10.1016/B978-0-12-819092-0.00025-X. ISBN 9780128190920.

Kim SJ, Kim HS, Seo YR. Understanding of ROS-inducing strategy in anticancer therapy. Oxid. Med. Cell Longev. 2019;2019:5381692. doi: 10.1155/2019/5381692. PubMed DOI PMC

Wallenberg M, Olm E, Hebert C, Björnstedt M, Fernandes AP. Selenium compounds are substrates for glutaredoxins: A novel pathway for selenium metabolism and a potential mechanism for selenium-mediated cytotoxicity. Biochem. J. 2010;429:85–93. doi: 10.1042/bj20100368. PubMed DOI

Misra S, Boylan M, Selvam A, Spallholz JE, Björnstedt M. Redox-active selenium compounds—From toxicity and cell death to cancer treatment. Nutrients. 2015;7:3536–3556. doi: 10.3390/nu7053536. PubMed DOI PMC

Brozmanová J, Mániková D, Vlčková V, Chovanec M. Selenium: a double-edged sword for defense and offence in cancer. Arch Toxicol. 2010;84:919–938. doi: 10.1007/s00204-010-0595-8. PubMed DOI

Doering M, et al. Synthesis and selective anticancer activity of organochalcogen based redox catalysts. J. Med. Chem. 2010;53:6954–6963. doi: 10.1021/jm100576z. PubMed DOI

Bartolini D, Galli F. The functional interactome of GSTP: A regulatory biomolecular network at the interface with the Nrf2 adaption response to oxidative stress. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2016;1019:29–44. doi: 10.1016/j.jchromb.2016.02.002. PubMed DOI

Palmeira A, Sousa E, Vasconcelos MH, Pinto MM. Three decades of P-gp inhibitors: Skimming through several generations and scaffolds. Curr. Med. Chem. 2012;19:1946–2025. doi: 10.2174/092986712800167392. PubMed DOI

Spengler G, Gajdács M, Marć MA, Domínguez-Álvarez E, Sanmartín C. Organoselenium compounds as novel adjuvants of chemotherapy drugs—A promising approach to fight cancer drug resistance. Molecules. 2019;24:336. doi: 10.3390/molecules24020336. PubMed DOI PMC

Szemerédi N, et al. Cyano- and ketone-containing selenoesters as multi-target compounds against resistant cancers. Cancers. 2021;13:4563. doi: 10.3390/cancers13184563. PubMed DOI PMC

Kannan P, et al. The “Specific” P-glycoprotein inhibitor tariquidar is also a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2) ACS Chem. Neurosci. 2011;2:82–89. doi: 10.1021/cn100078a. PubMed DOI PMC

Dobiasova S, et al. Multidrug resistance modulation activity of silybin derivatives and their anti-inflammatory potential. Antioxidants. 2020 doi: 10.3390/antiox9050455. PubMed DOI PMC

Ganesan M, et al. Phytochemicals reverse P-glycoprotein mediated multidrug resistance via signal transduction pathways. Biomed. Pharmacother. 2021;139:111632. doi: 10.1016/j.biopha.2021.111632. PubMed DOI

Mao Z, et al. Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells. Biomed. Pharmacother. 2014;68:179–183. doi: 10.1016/j.biopha.2013.10.003. PubMed DOI

Chen T, et al. Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway. Cancer Biol. Ther. 2015;16:106–114. doi: 10.4161/15384047.2014.987062. PubMed DOI PMC

Antoni D, Burckel H, Josset E, Noel G. Three-dimensional cell culture: A breakthrough in vivo. Int. J. Mol. Sci. 2015;16:5517–5527. doi: 10.3390/ijms16035517. PubMed DOI PMC

Chaicharoenaudomrung N, Kunhorm P, Noisa P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World J. Stem Cells. 2019;11:1065–1083. doi: 10.4252/wjsc.v11.i12.1065. PubMed DOI PMC

Wang J, Seebacher N, Shi H, Kan Q, Duan Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017;8:84559–84571. doi: 10.18632/oncotarget.19187. PubMed DOI PMC

Ruiz MC, Kljun J, Turel I, Di Virgilio AL, León IE. Comparative antitumor studies of organoruthenium complexes with 8-hydroxyquinolines on 2D and 3D cell models of bone, lung and breast cancer. Metallomics. 2019;11:666–675. doi: 10.1039/C8MT00369F. PubMed DOI

Cho K, Wang X, Nie S, Chen ZG, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 2008;14:1310–1316. doi: 10.1158/1078-0432.Ccr-07-1441. PubMed DOI

Sonkusre P. Specificity of biogenic selenium nanoparticles for prostate cancer therapy with reduced risk of toxicity: An in vitro and in vivo study. Front. Oncol. 2019;9:1541. doi: 10.3389/fonc.2019.01541. PubMed DOI PMC

Cali DMAJJ. Identify P-glycoprotein substrates and inhibitors with the rapid, HTS Pgp-Glo™ assay system. Promega Notes. 2007;96:11–14.

Viktorová J, et al. Lemon grass essential oil does not modulate cancer cells multidrug resistance by citral-its dominant and strongly antimicrobial compound. Foods (Basel, Switzerland) 2020;9:585. doi: 10.3390/foods9050585. PubMed DOI PMC

Bustin SA, et al. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 2009;55:611–622. doi: 10.1373/clinchem.2008.112797. PubMed DOI