TRX/TRXR1 ENZİM SİSTEMİNİN BİYOKİMYASI VE MEME KANSERİ KEMOTERAPİSİNDE DOĞAL ÜRÜN KAYNAKLI MODÜLASYONU
Özet
Tiyoredoksin redüktaz 1 (TrxR1/TXNRD1), NADPH’den aldığı elektronları tiyoredoksine aktararak hücresel redoks homeostazının sürdürülmesinde kritik rol oynayan, selenosistein içeren bir flavoenzimdir. Katalitik C-terminal selenosistein kalıntısının yüksek nükleofilikliği ve elektrofillere karşı reaktivitesi, TrxR1’in kimyasal olarak dikkat çekici bir enzim olmasını sağlarken, bu özelliği enzimi son yıllarda redoks biyolojisi ve kanser araştırmalarında giderek önem kazanan bir moleküler hedef haline getirmiştir. Özellikle enzimin erişilebilir C-terminal selenosistein kalıntısı, elektrofilik doğal ürünler açısından potansiyel bir terapötik hedef niteliğindedir. Meme kanserinde artmış TXNRD1/TrxR1 ekspresyonunun kötü prognoz ve tedavi yanıtıyla ilişkilendirilmesi, TrxR1 aracılı redoks sisteminin kemodirençteki olası rolüne yönelik ilgiyi artırmıştır. Meme kanserinde artmış TXNRD1/TrxR1 ekspresyonunun kötü prognoz ve bağımsız prognostik değer ile ilişkilendirilmesi, bu redoks sistemini kemodirenç açısından önemli bir hedef haline getirmektedir. Bununla birlikte, TrxR1/Trx ekseninin kemoterapi yanıtındaki etkisi bağlama bağımlıdır. İndirgenmiş Trx’nin ASK1 aktivasyonunu baskılayarak apoptozu sınırlandırabildiği bildirilirken, bazı modellerde TrxR1 aracılı redoks süreçlerinin antrasiklinlerin redoks döngüsüne ve p53-bağımlı apoptotik yanıtın oluşumuna katkıda bulunabildiği gösterilmiştir. Kurkumin, piperlongumin ve şikonin gibi doğal bileşiklerin TrxR1'in C-terminal selenosistein bölgesini hedefleyerek enzimi geri dönüşümsüz biçimde inhibe ettiği ve pro-oksidan SecTRAP oluşumunu tetiklediği bildirilmiştir. Bununla birlikte, vulpinik asit, difraktaik asit ve evernik asit gibi liken kaynaklı sekonder metabolitlerin meme kanseri hücrelerinde TrxR1 aktivitesini azaltmasına rağmen, bu bileşiklerin selenosistein bölgesiyle doğrudan etkileşimi henüz ortaya konmamıştır. Ayrıca, doğal ürün–kemoterapötik kombinasyonlarında elde edilen yanıtların bileşiğe ve kemoterapötik ajana göre değişkenlik göstermesi, sinerjinin nicel olarak ve her kombinasyon için ayrı değerlendirilmesi gerektiğini göstermektedir. Mevcut veriler; hedef doğrulama, izoform ve hücre içi kompartman farklılıkları, redoks sinyal ağlarının kapsamlı değerlendirilmemesi, antrasiklin kombinasyonlarına ilişkin sınırlı kanıt ve GSH/Nrf2 gibi telafi edici mekanizmaların yanı sıra normal dokularda TrxR1'in fizyolojik öneminden kaynaklanan güvenlik kaygıları nedeniyle alanın hâlen araştırma ve hipotez oluşturma aşamasında olduğunu göstermektedir.
Anahtar Kelimeler: doğal ürünler, kemodirenç, meme kanseri, TrxR1, Trx
Konu Alanı: Biyoloji -> Biyoloji (diğer) -> Biyokimya
Alkan, A. H., Ensoy, M., & Cansaran-Duman, D. (2024). A new therapeutic strategy for luminal A-breast cancer treatment: Vulpinic acid as an anti-neoplastic agent induces ferroptosis and apoptosis mechanisms. Medical Oncology, 41, Article 229. https://doi.org/10.1007/s12032-024-02473-8
Arnér, E. S. J., & 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
Bhatia, M., McGrath, K. L., Di Trapani, G., Charoentong, P., Shah, F., King, M. M., Clarke, F. M., & Tonissen, K. F. (2016). The thioredoxin system in breast cancer cell invasion and migration. Redox Biology, 8, 68–78. https://doi.org/10.1016/j.redox.2015.12.004
Biaglow, J. E., & Miller, R. A. (2005). The thioredoxin reductase/thioredoxin system: Novel redox targets for cancer therapy. Cancer Biology & Therapy, 4(1), 6–13. https://doi.org/10.4161/cbt.4.1.1434
Bian, M., Fan, R., Zhao, S., & Liu, W. (2019). Targeting the thioredoxin system as a strategy for cancer therapy. Journal of Medicinal Chemistry, 62(16), 7309–7321. https://doi.org/10.1021/acs.jmedchem.8b01595
Budak, B., Kalın, Ş. N., & Yapça, Ö. E. (2024). Antiproliferative, antimigratory, and apoptotic effects of diffractaic and vulpinic acids as thioredoxin reductase 1 inhibitors on cervical cancer. Naunyn-Schmiedeberg's Archives of Pharmacology, 397(3), 1525–1535. https://doi.org/10.1007/s00210-023-02698-w
Cadenas, C., Franckenstein, D., Schmidt, M., Gehrmann, M., Hermes, M., Geppert, B., ... & Hengstler, J. G. (2010). Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast cancer research, 12(3), R44. https://doi.org/10.1186/bcr2599
Cansaran-Duman, D., Yangın, S., & Çolak, B. (2021). The role of vulpinic acid as a natural compound in the regulation of breast cancer-associated miRNAs. Biological Research, 54. https://doi.org/10.1186/s40659-021-00360-4
Chen, Z. H., Saito, Y., Yoshida, Y., Sekine, A., Noguchi, N., & Niki, E. (2005). 4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2. Journal of Biological Chemistry, 280, 41921–41927. https://doi.org/10.1074/jbc.M508556200
Cheng, Q., Sandalova, T., Lindqvist, Y., & Arner, E. S. (2009). Crystal structure and catalysis of the selenoprotein thioredoxin reductase 1. Journal of Biological Chemistry, 284(6), 3998-4008. https://doi.org/10.1074/jbc.M807068200
Chou, T.-C. (2006). Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacological Reviews, 58(3), 621–681. https://doi.org/10.1124/pr.58.3.10
Circu, M. L., & Aw, T. Y. (2010). Reactive oxygen species, cellular redox systems, and apoptosis. Free Radical Biology and Medicine, 48, 749–762. https://doi.org/10.1016/j.freeradbiomed.2009.12.022
Evison, B. J., Sleebs, B. E., Watson, K. G., Phillips, D. R., & Cutts, S. M. (2016). Mitoxantrone, more than just another topoisomerase II poison. Medicinal Research Reviews, 36(2), 248–299. https://doi.org/10.1002/med.21364
Fang, J., Lu, J., & Holmgren, A. (2005). Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. Journal of biological chemistry, 280(26), 25284-25290. https://doi.org/10.1074/jbc.M414645200
Fritz-Wolf, K., Kehr, S., Stumpf, M., Rahlfs, S., & Becker, K. (2011). Crystal structure of the human thioredoxin reductase–thioredoxin complex. Nature Communications, 2, Article 383. https://doi.org/10.1038/ncomms1382
Galanty, A., Zagrodzki, P., Gdula-Argasińska, J., Grabowska, K., Koczurkiewicz-Adamczyk, P., Wróbel-Biedrawa, D., Podolak, I., Pękala, E., & Paśko, P. (2021). A comparative survey of anti-melanoma and anti-inflammatory potential of usnic acid enantiomers—A comprehensive in vitro approach. Pharmaceuticals, 14(9), 945. https://doi.org/10.3390/ph14090945
Gencheva, R., & Arnér, E. S. (2022). Thioredoxin reductase inhibition for cancer therapy. Annual Review of Pharmacology and Toxicology, 62, 177-196. https://doi.org/10.1146/annurev-pharmtox-052220-102509
Gewirtz, D. A. (1999). A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochemical Pharmacology, 57(7), 727–741. https://doi.org/10.1016/S0006-2952(98)00307-4
Gromer, S., Johansson, L., Bauer, H., Arscott, L. D., Rauch, S., Ballou, D. P., Williams, C. H., Jr., Schirmer, R. H., & Arnér, E. S. J. (2003). Active sites of thioredoxin reductases: Why selenoproteins? Proceedings of the National Academy of Sciences, 100(22), 12618–12623. https://doi.org/10.1073/pnas.2134510100
Günaydın, Ş., Sulukoğlu, E. K., Kalın, Ş. N., Altay, A., & Budak, H. (2023). Diffractaic acid exhibits thioredoxin reductase 1 inhibition in lung cancer A549 cells. Journal of Applied Toxicology, 43(11), 1676–1685. https://doi.org/10.1002/jat.4505
Harris, I. S., Treloar, A. E., Inoue, S., Sasaki, M., Gorrini, C., Lee, K. C., Yung, K. Y., Brenner, D., Knobbe-Thomsen, C. B., Cox, M. A., Elia, A., Berger, T., Cescon, D. W., Adeoye, A., Brüstle, A., Molyneux, S. D., Mason, J. M., Li, W. Y., Yamamoto, K., . . . Mak, T. W. (2015). Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell, 27(2), 211–222. https://doi.org/10.1016/j.ccell.2014.11.019
Holmgren, A. (1985). Thioredoxin. Annual Review of Biochemistry, 54, 237–271. https://doi.org/10.1146/annurev.bi.54.070185.001321
Jakupoglu, C., Przemeck, G. K. H., Schneider, M., Moreno, S. G., Mayr, N., Hatzopoulos, A. K., de Angelis, M. H., Wurst, W., Bornkamm, G. W., Brielmeier, M., & Conrad, M. (2005). Cytoplasmic thioredoxin reductase is essential for embryogenesis but dispensable for cardiac development. Molecular and Cellular Biology, 25(5), 1980–1988. https://doi.org/10.1128/MCB.25.5.1980-1988.2005
Kağan Yeniçeri, E. K., & Altay, A. (2024). The combined effect of vulpinic acid and doxorubicin in breast cancer MCF-7 cells. Erzincan Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 17, 164–173. https://doi.org/10.18185/erzifbed.1376859
Kalın, Ş. N., Altay, A., & Budak, H. (2022). Diffractaic acid, a novel TrxR1 inhibitor, induces cytotoxicity, apoptosis, and antimigration in human breast cancer cells. Chemico-Biological Interactions, 361, 109984. https://doi.org/10.1016/j.cbi.2022.109984
Kalın, Ş. N., Altay, A., & Budak, H. (2022). Inhibition of thioredoxin reductase 1 by vulpinic acid suppresses the proliferation and migration of human breast carcinoma. Life Sciences, 310, 121093. https://doi.org/10.1016/j.lfs.2022.121093
Kalın, Ş. N., Altay, A., & Budak, H. (2023). Effect of evernic acid on human breast cancer MCF-7 and MDA-MB-453 cell lines via thioredoxin reductase 1: A molecular approach. Journal of Applied Toxicology, 43(8), 1148–1158. https://doi.org/10.1002/jat.4451
Kennedy, L., Sandhu, J. K., Harper, M.-E., & Cuperlovic-Culf, M. (2020). Role of glutathione in cancer: From mechanisms to therapies. Biomolecules, 10(10), 1429. https://doi.org/10.3390/biom10101429
Lu, J., & Holmgren, A. (2014). The thioredoxin antioxidant system. Free radical biology and medicine, 66, 75-87. https://doi.org/10.1016/j.freeradbiomed.2013.07.036
Lu, J., Chew, E.-H., & Holmgren, A. (2007). Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proceedings of the National Academy of Sciences, 104, 12288–12293. https://doi.org/10.1073/pnas.0701549104
Mandal, P. K., Schneider, M., Kölle, P., Kuhlencordt, P., Förster, H., Beck, H., Bornkamm, G. W., & Conrad, M. (2010). Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation. Cancer Research, 70(22), 9505–9514. https://doi.org/10.1158/0008-5472.CAN-10-1509
McDonald, C., Muhlbauer, J., Perlmutter, G., Taparra, K., & Phelan, S. A. (2014). Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity. International Journal of Oncology, 45(1), 219-226. https://doi.org/10.3892/ijo.2014.2398
Mohammadi, F., Soltani, A., Ghahremanloo, A., Javid, H., & Hashemy, S. I. (2019). The thioredoxin system and cancer therapy: A review. Cancer Chemotherapy and Pharmacology, 84(5), 925–935. https://doi.org/10.1007/s00280-019-03912-4
NavaneethaKrishnan, S., Rosales, J. L., & Lee, K.-Y. (2019). ROS-mediated cancer cell killing through dietary phytochemicals. Oxidative Medicine and Cellular Longevity, 2019, Article 9051542. https://doi.org/10.1155/2019/9051542
Ozgencli, I., Budak, H., Ciftci, M., & Anar, M. (2018). Lichen acids may be used as a potential drug for cancer therapy; by inhibiting mitochondrial thioredoxin reductase purified from rat lung. Anti-Cancer Agents in Medicinal Chemistry, 18(11), 1599–1605. https://doi.org/10.2174/1871520618666180525095520
Ravi, D., Muniyappa, H., & Das, K. C. (2005). Endogenous thioredoxin is required for redox cycling of anthracyclines and p53-dependent apoptosis in cancer cells. Journal of Biological Chemistry, 280(48), 40084-40096. https://doi.org/10.1074/jbc.M507192200
Roder, C., & Thomson, M. J. (2015). Auranofin: Repurposing an old drug for a golden new age. Drugs in R&D, 15(1), 13–20. https://doi.org/10.1007/s40268-015-0083-y
Saghatelyan, T., Tananyan, A., Janoyan, N., Tadevosyan, A., Petrosyan, H., Hovhannisyan, A., Hayrapetyan, L., Arustamyan, M., Arnhold, J., Rotmann, A.-R., Hovhannisyan, A., & Panossian, A. (2020). Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine, 70, 153218. https://doi.org/10.1016/j.phymed.2020.153218
Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., ... & Ichijo, H. (1998). Mammalian thioredoxin is a direct inhibitor of apoptosis signal‐regulating kinase (ASK) 1. The EMBO journal, 17(9), 2596-2606. https://doi.org/10.1093/emboj/17.9.2596
Sarkar, E., Kotiya, A., Bhuyan, R., Raza, S. T., Misra, A., Ahmad, R., & Mahdi, A. A. (2025). Curcumin chemo-sensitizes intrinsic apoptosis through ROS-mediated mitochondrial hyperpolarization and DNA damage in breast cancer cells. Cellular Signalling, 128, 111637. https://doi.org/10.1016/j.cellsig.2025.111637
Sasada, T., Nakamura, H., Ueda, S., Sato, N., Kitaoka, Y., Gon, Y., Takabayashi, A., Spyrou, G., Holmgren, A., & Yodoi, J. (1999). Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum (II). Free Radical Biology and Medicine, 27(5–6), 504–514. https://doi.org/10.1016/S0891-5849(99)00101-X
Seitz, R., Tümen, D., Kunst, C., Heumann, P., Schmid, S., Kandulski, A., Müller, M., & Gülow, K. (2024). Exploring the thioredoxin system as a therapeutic target in cancer: Mechanisms and implications. Antioxidants, 13(9), 1078. https://doi.org/10.3390/antiox13091078
Sinha, P., Hütter, G., Köttgen, E., Dietel, M., Schadendorf, D., & Lage, H. (1998). Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells. Journal of Biochemical and Biophysical Methods, 37(3), 105–116. https://doi.org/10.1016/S0165-022X(98)00020-7
Solárová, Z., Liskova, A., Samec, M., Kubatka, P., Büsselberg, D., & Solár, P. (2020). Anticancer potential of lichens’ secondary metabolites. Biomolecules, 10(1), 87. https://doi.org/10.3390/biom10010087
Sulukoğlu, E. K., Günaydın, Ş., Kalın, Ş. N., Altay, A., & Budak, H. (2024). Diffractaic acid exerts anti-cancer effects on hepatocellular carcinoma HepG2 cells by inducing apoptosis and suppressing migration through targeting thioredoxin reductase 1. Naunyn-Schmiedeberg's Archives of Pharmacology, 397, 5745–5755. https://doi.org/10.1007/s00210-024-02980-5
Sung, H., Ferlay, J., Siegel, RL, Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Küresel kanser istatistikleri 2020: 185 ülkede 36 kanser için dünya çapındaki insidans ve mortaliteye ilişkin GLOBOCAN tahminleri. CA: klinisyenler için bir kanser dergisi, 71 (3), 209-249. https://doi.org/10.3322/caac.21660
Toraman, E., Kalın, Ş. N., Bayındırlı, K. N., Günaydın, Ş., Keleş, F., Altay, A., & Budak, H. (2026). Pro-oxidant effect of lobaric acid as a therapeutic strategy against breast cancer: A molecular perspective. Molecular Biology Reports, 53, Article 520. https://doi.org/10.1007/s11033-026-11688-z
Trachootham, D., Alexandre, J., & Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?. Nature reviews Drug discovery, 8(7), 579-591. https://doi.org/10.1038/nrd2803
Urig, S., & Becker, K. (2006). On the potential of thioredoxin reductase inhibitors for cancer therapy. Seminars in Cancer Biology, 16(6), 452–465. https://doi.org/10.1016/j.semcancer.2006.09.004
Wang, X. J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., ... & Zhang, D. D. (2008). Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis, 29(6), 1235-1243. https://doi.org/10.1093/carcin/bgn095
Woolston, C. M., Zhang, L., Storr, S. J., Al-Attar, A., Shehata, M., Ellis, I. O., ... & Martin, S. G. (2012). The prognostic and predictive power of redox protein expression for anthracycline-based chemotherapy response in locally advanced breast cancer. Modern Pathology, 25(8), 1106-1116. https://doi.org/10.1038/modpathol.2012.60
Yang, Y., Sun, S., Xu, W., Zhang, Y., Yang, R., Ma, K., Zhang, J., & Xu, J. (2022). Piperlongumine inhibits thioredoxin reductase 1 by targeting selenocysteine residues and sensitizes cancer cells to erastin. Antioxidants, 11(4), 710. https://doi.org/10.3390/antiox11040710
Yokomizo, A., Ono, M., Nanri, H., Makino, Y., Ohga, T., Wada, M., Okamoto, T., Yodoi, J., Kuwano, M., & Kohno, K. (1995). Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Research, 55(19), 4293–4296.
Yue, J., & López, J. M. (2020). Understanding MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346. https://doi.org/10.3390/ijms21072346
Zhang, Y., Sun, S., Xu, W., Yang, R., Yang, Y., Guo, J., ... & Xu, J. (2022). Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling. Free Radical Biology and Medicine, 180, 52-62. https://doi.org/10.1016/j.freeradbiomed.2021.12.314
Zhong, L., & Holmgren, A. (2000). Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. Journal of Biological Chemistry, 275, 18121–18128. https://doi.org/10.1074/jbc.M000690200
Zhong, L., Arnér, E. S. J., Ljung, J., Åslund, F., & Holmgren, A. (1998). Rat and calf thioredoxin reductase are homologous to glutathione reductase with a carboxyl-terminal elongation containing a conserved catalytically active penultimate selenocysteine residue. Journal of Biological Chemistry, 273(15), 8581–8591. https://doi.org/10.1074/jbc.273.15.8581
KAĞAN YENİÇERİ, E. K. (2026). TRX/TRXR1 ENZİM SİSTEMİNİN BİYOKİMYASI VE MEME KANSERİ KEMOTERAPİSİNDE DOĞAL ÜRÜN KAYNAKLI MODÜLASYONU. In ÖZDOKUR, K. V. (Ed.), Çağdaş Kimya Araştırmaları ve Multidisipliner Uygulamaları-Contemporary Chemistry Research and Multidisciplinary Applications (pp. -). Vizetek Yayıncılık. https://doi.org/10.54637/vizetek.9786253824792
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