Evaluation of Some Antidepressants as Inhibitors of Thioredoxin Reductase Enzyme, which is an Anticancer Target

Year 2023, Issue: 51, 224 - 228, 31.08.2023

İkranur Felek Ebru Akkemik

https://doi.org/10.31590/ejosat.1293053

Abstract

Thioredoxin reductase (TrxR) is an enzyme that is involved in many metabolic pathways from detoxification to reduction of radicals by catalyzing the reduction of thioredoxin, and is therefore associated with many physiological processes, including cancer. Inhibitors of this enzyme are considered anticancer targets. In past studies, some antidepressants have been found to have anticancer effects through various mechanisms, and therefore the reuse of antidepressants as anticancer drugs has attracted the attention of researchers. In this study, it was aimed to investigate the inhibition effect of some antidepressants (neferine (1), amoxapine (2), mirtazapine (3), agomelatine (4), trazodone hydrochloride (5), amitrptyline hydrochloride (6)) on cytosolic rat liver TrxR activity. The inhibition effects of these molecules were determined by IC50 and Ki values. 1 (IC50:220 µM, Ki: 1.3±0.79 µM), 2 (IC50:337 µM, Ki: 5.2±2.1 µM), 3 (IC50:487 µM, Ki: 5.6±1.99 µM) and 4 (IC50: 545 µM, Ki: 7.0±1.83 µM) exhibited potent inhibition effect on cytosolic rat liver TrxR. As a result, it was hoped that these results might contribute to both explaining the anticancer mechanism of these antidepressants and synthesizing new TrxR inhibitors with anticancer effects

Keywords

Antidepressant, cancer, thioredoxin reductase

Supporting Institution

The authors appreciate the Scientific Research Council of Siirt University for their support of the Project.

Project Number

Project No: 2017-SİÜMÜH-44

Thanks

We would like to thank Deryanur KILIÇ for her contributions.

Bazı Antidepresanların Antikanser Hedefi Olan Tioredoksin Redüktaz Enziminin İnhibitörleri Olarak Değerlendirilmesi

Abstract

Tioredoksin redüktaz (TrxR), tioredoksinin indirgenmesini katalize ederek detoksifikasyondan radikallerin indirgenmesine kadar pek çok metabolik yolda yer almaktadır. Bu nedenle kanser de dahil olmak üzere birçok fizyolojik süreçle ilişkili bir enzimdir. Bu enzimin inhibitörleri antikanser hedefleri olarak kabul edilir. Geçmişte yapılan çalışmalarda bazı antidepresanların çeşitli mekanizmalar yoluyla antikanser etki gösterdiği bulunmuş ve bu nedenle antidepresanların antikanser ilaç olarak tekrar kullanılması araştırmacıların ilgisini çekmiştir. Bu çalışmada bazı antidepresanların (neferin (1), amoksapin (2), mirtazapin (3), agomelatin (4), trazodon hidroklorür (5), amitrptilin hidroklorür (6)) sitozolik hormon üzerindeki inhibisyon etkisinin araştırılması amaçlanmıştır. Sıçan karaciğeri TrxR aktivitesi üzerine bu moleküllerin inhibisyon etkileri IC50 ve Ki değerleri ile belirlendi. 1 (IC50:220 µM, Ki: 1,3±0,79 µM), 2 (IC50:337 µM, Ki: 5,2±2,1 µM), 3 (IC50:487 µM, Ki: 5,6±1,99 µM) ve 4 (IC50: 545) uM, Ki: 7,0±1,83 uM), sitozolik sıçan karaciğeri TrxR üzerinde güçlü inhibisyon etkisi sergiledi. Sonuç olarak, bu sonuçların hem bu antidepresanların antikanser mekanizmasını açıklamaya hem de antikanser etkileri olan yeni TrxR inhibitörlerinin sentezlenmesine katkı sağlayacağı düşünülmektedir.

Keywords

Antidepresan, kanser, tioredoksin redüktaz.

Project Number

Project No: 2017-SİÜMÜH-44

References

• Arnér, E. S., & Holmgren, A. (2000). Physiological functions of thioredoxin and thioredoxin reductase. European journal of biochemistry, 267(20), 6102–6109. https://doi.org/10.1046/j.1432-1327.2000.01701.x
• Becker, K., Gromer, S., Schirmer, R. H., & Müller, S. (2000). Thioredoxin reductase as a pathophysiological factor and drug target. European journal of biochemistry, 267(20), 6118–6125. https://doi.org/10.1046/j.1432-1327.2000.01703.x
• Bilici, M., Cayir, K., Tekin, S. B., Gundogdu, C., Albayrak, A., Suleyman, B., Ozogul, B., Erdemci, B., & Suleyman, H. (2012). Effect of mirtazapine on MNNG-induced gastric adenocarcinoma in rats. Asian Pacific journal of cancer prevention: APJCP, 13(10), 4897–4900. https://doi.org/10.7314/apjcp.2012.13.10.4897
• Bjørklund, G., Zou, L., Wang, J., Chasapis, C. T., & Peana, M. (2021). Thioredoxin reductase as a pharmacological target. Pharmacological research, 174, 105854. https://doi.org/10.1016/j.phrs.2021.105854
• Boumis, G., Giardina, G., Angelucci, F., Bellelli, A., Brunori, M., Dimastrogiovanni, D., Saccoccia, F., & Miele, A. E. (2012). Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target. Biochemical and biophysical research communications, 425(4), 806–811. https://doi.org/10.1016/j.bbrc.2012.07.156
• Cimini, A., Gentile, R., Angelucci, F., Benedetti, E., Pitari, G., Giordano, A., & Ippoliti, R. (2013). Neuroprotective effects of PrxI over-expression in an in vitro human Alzheimer's disease model. Journal of cellular biochemistry, 114(3), 708–715. https://doi.org/10.1002/jcb.24412
• Collet, J. F., & Messens, J. (2010). Structure, function, and mechanism of thioredoxin proteins. Antioxidants & redox signaling, 13(8), 1205–1216. https://doi.org/10.1089/ars.2010.3114
• Cordero, M. D., Sánchez-Alcázar, J. A., Bautista-Ferrufino, M. R., Carmona-López, M. I., Illanes, M., Ríos, M. J., Garrido-Maraver, J., Alcudia, A., Navas, P., & de Miguel, M. (2010). Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs. Anti-cancer drugs, 21(10), 932–944. https://doi.org/10.1097/CAD.0b013e32833ed5f7
• Fang, C. K., Chen, H. W., Chiang, I. T., Chen, C. C., Liao, J. F., Su, T. P., Tung, C. Y., Uchitomi, Y., & Hwang, J. J. (2012). Mirtazapine inhibits tumor growth via immune response and serotonergic system. PloS one, 7(7), e38886. https://doi.org/10.1371/journal.pone.0038886
• Fang, Y., Liao, G., & Yu, B. (2019). LSD1/KDM1A inhibitors in clinical trials: advances and prospects. Journal of hematology & oncology, 12(1), 129. https://doi.org/10.1186/s13045-019-0811-9
• Frick, L. R., & Rapanelli, M. (2013). Antidepressants: influence on cancer and immunity?. Life sciences, 92(10), 525–532. https://doi.org/10.1016/j.lfs.2013.01.020
• Galeti, A., de Oliveira, J., Pinheiro, M., dos Santos, M., Colombo, J., Chuffa, L. and Zuccari, D. 2021. Verification of agomelatine in comparison with melatonin as a therapeutic agent to treat breast cancer. Melatonin Research. 4, 1 (Jan. 2021), 141-151. DOI: https://doi.org/https://doi.org/10.32794/mr11250087.
• Higgins, S. C., & Pilkington, G. J. (2010). The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma. Anticancer research, 30(2), 391–397. https://ar.iiarjournals.org/content/30/2/391
• Hill, K. E., McCollum, G. W., & Burk, R. F. (1997). Determination of thioredoxin reductase activity in rat liver supernatant. Analytical biochemistry, 253(1), 123–125. https://doi.org/10.1006/abio.1997.2373
• Holmgren, A., & Lu, J. (2010). Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochemical and biophysical research communications, 396(1), 120–124. https://doi.org/10.1016/j.bbrc.2010.03.083
• Kim, S. J., Miyoshi, Y., Taguchi, T., Tamaki, Y., Nakamura, H., Yodoi, J., Kato, K., & Noguchi, S. (2005). High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 11(23), 8425–8430. https://doi.org/10.1158/1078-0432.CCR-05-0449
• Kuntz, A. N., Davioud-Charvet, E., Sayed, A. A., Califf, L. L., Dessolin, J., Arnér, E. S., & Williams, D. L. (2007). Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target. PLoS medicine, 4(6), e206. https://doi.org/10.1371/journal.pmed.0040206
• Lineweaver, H. & Burk, D. (1934). The Determination of Enzyme Dissociation Constant, J. Am. Chem. Soc. 56, 3, 658–666, https://doi.org/10.1021/ja01318a036
• Low, Z. Y., Farouk, I. A., & Lal, S. K. (2020). Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak. Viruses, 12(9), 1058. https://doi.org/10.3390/v12091058
• Marthandam Asokan, S., Mariappan, R., Muthusamy, S., & Velmurugan, B. K. (2018). Pharmacological benefits of neferine-A comprehensive review. Life sciences, 199, 60–70. https://doi.org/10.1016/j.lfs.2018.02.032
• Parker, K. A., Glaysher, S., Hurren, J., Knight, L. A., McCormick, D., Suovouri, A., Amberger-Murphy, V., Pilkington, G. J., & Cree, I. A. (2012). The effect of tricyclic antidepressants on cutaneous melanoma cell lines and primary cell cultures. Anti-cancer drugs, 23(1), 65–69. https://doi.org/10.1097/CAD.0b013e32834b1894.
• Patwardhan, R. S., Sharma, D., & Sandur, S. K. (2022). Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer. Translational oncology, 17, 101341. Advance online publication. https://doi.org/10.1016/j.tranon.2022.101341
• Prast-Nielsen, S., Huang, HH., Williams, D.L. (2011). Thioredoxin glutathione reductase: its role in redox biology and potential as a target for drugs against neglected diseases. Biochim Biophys Acta. Dec;1810(12):1262-71. doi: 10.1016/j.bbagen.2011.06.024.
• Riess, J. W., Jahchan, N. S., Das, M., Zach Koontz, M., Kunz, P. L., Wakelee, H. A., Schatzberg, A., Sage, J., & Neal, J. W. (2020). A Phase Iia Study Reposıtıonıng Desipramine In Small Cell Lung Cancer and other High-Grade Neuroendocrıne Tumors. Cancer treatment and research communications, 23, 100174. Advance online publication. https://doi.org/10.1016/j.ctarc.2020.100174
• Saccoccia, F., Angelucci, F., Boumis, G., Carotti, D., Desiato, G., Miele, A.E., Bellelli, A. (2014). Thioredoxin reductase and its inhibitors. Curr Protein Pept Sci. 15(6):621-46. doi: 10.2174/1389203715666140530091910.
• Saccoccia, F., Di Micco, P., Boumis, G., Brunori, M., Koutris, I., Miele, A. E., Morea, V., Sriratana, P., Williams, D. L., Bellelli, A., & Angelucci, F. (2012). Moonlighting by different stressors: crystal structure of the chaperone species of a 2-Cys peroxiredoxin. Structure (London, England : 1993), 20(3), 429–439. https://doi.org/10.1016/j.str.2012.01.004.
• Selenius, M., Rundlöf, A. K., Olm, E., Fernandes, A. P., & Björnstedt, M. (2010). Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxidants & redox signaling, 12(7), 867–880. https://doi.org/10.1089/ars.2009.2884
• Tonissen, K. F., & Di Trapani, G. (2009). Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy. Molecular nutrition & food research, 53(1), 87–103. https://doi.org/10.1002/mnfr.200700492
• Uzawa, K., Kasamatsu, A., Shimizu, T., Saito, Y., Baba, T., Sakuma, K., Fushimi, K., Sakamoto, Y., Ogawara, K., Shiiba, M., & Tanzawa, H. (2014). Suppression of metastasis by mirtazapine via restoration of the Lin-7C/β-catenin pathway in human cancer cells. Scientific reports, 4, 5433. https://doi.org/10.1038/srep05433
• Yeh, K. C., Hung, C. F., Lin, Y. F., Chang, C., Pai, M. S., & Wang, S. J. (2020). Neferine, a bisbenzylisoquinoline alkaloid of Nelumbo nucifera, inhibits glutamate release in rat cerebrocortical nerve terminals through 5-HT1A receptors. European journal of pharmacology, 889, 173589. https://doi.org/10.1016/j.ejphar.2020.173589
• Zhang, J., Li, X., Han, X., Liu, R., & Fang, J. (2017). Targeting the Thioredoxin System for Cancer Therapy. Trends in pharmacological sciences, 38(9), 794–808. https://doi.org/10.1016/j.tips.2017.06.001
• Zhang, X., Feng, P., Gao, X., Wang, B., Gou, C., & Bian, R. (2020). In vitro inhibitory effects of cepharanthine on human liver cytochrome P450 enzymes. Pharmaceutical biology, 58(1), 247–252. https://doi.org/10.1080/13880209.2020.1741650
• Zhang, Z., Du, X., Zhao, C., Cao, B., Zhao, Y., & Mao, X. (2013). The antidepressant amitriptyline shows potent therapeutic activity against multiple myeloma. Anti-cancer drugs, 24(8), 792–798. https://doi.org/10.1097/CAD.0b013e3283628c21