RENAL HÜCRELERDE METOTREKSAT KAYNAKLI SİTOTOKSİSİTE: KURKUMİN’İN KORUYUCU ROLÜ

Year 2020, , 281 - 292, 21.06.2020

Bilal Çiğ

https://doi.org/10.33715/inonusaglik.727031

Cited By: 1

Abstract

Metotreksat (MET), akciğer, meme kanserleri ve lenfoma gibi çeşitli malignitelerin tedavisinde kullanılmaktadır. Bu neoplastik ajanın hepatorenal toksisite gibi çeşitli komplikasyonlara neden olması onun tedavide kullanımını sınırlamaktadır. Antiinflamatuvar etkileri çok iyi bilinen kurkumin (KUR)’in hepatorenal toksisite üzerindeki koruyucu etkileri literatürde ifade edilmiştir. Bu çalışmada metotreksat ile indüklenen oksidatif stres, proinflamatuar yanıtın kurkumin ile baskılanabileceğini varsaydık. Bu çalışma, metotreksat kaynaklı sitotoksisite ve oksidatif strese karşı kurkuminin koruyucu rolünü araştırmak için planlandı. Bu çalışmada metotreksat kaynaklı renal toksisite ve sonrasında gelişen moleküler olayları in-vitro araştırmak üzere fare böbrek kortikal toplama kanal hücreleri (mpkCCDc14) kullanıldı. Gruplar, Kontrol, KUR (10 μM ve 24 saat), MET (5 μM ve 24 saat) ve MET+KUR olarak dizayn edildi. Metotreksat kaynaklı oksidatif stres, mpkCCDc14 hücrelerinde mitokondriyal membran depolarizasyonu (MMD), sitozolik reaktif oksijen türleri (ROS) üretimi, apopitoz ve kaspaz-3, kaspaz-9 aktivasyon düzeyleri belirlenerek değerlendirildi. MET, oksidatif stresin hücre içinde artmasına neden olmasına rağmen, bu kurkumin tarafından azaltılmıştır. Kurkumin tedavisi, mitokondriyal disfonksiyonu düzenleyerek hücrelerde ROS oluşumunu bastırdı. Metotreksata maruz kalan hücrelerde apoptoz, kaspaz-3 ve kaspaz-9 aktiviteleri artmıştır. Bununla birlikte bu durum, kurkumin tedavisi ile modüle edildi. Sonuç olarak, metotreksat ile indüklenen oksidatif stres hücre hasarına ve proenflamatuar yanıta yol açarak kronik böbrek hastalığının ilerlemesinde mpkCCDc14 hücrelerinin rolünü güçlendirir. Kurkumin antioksidan, antienflamatuar ve anti-apopitotik etki ederek metotreksat kaynaklı sitozolik toksisiteye karşı yardımcı bir tedavi olabilir.

Keywords

Apoptoz, Kurkumin, Metotreksat, Oksidatif stress

Methotrexate-Induced Cytotoxicity in Renal Cells: The Protective Role of Curcumin

Abstract

Methotrexate (MET) is used in the treatment of various malignancies such as lung, breast cancers and lymphoma. The fact that it causes various complications such as hepatorenal toxicity limits its usage in treatment. The hepatorenal toxicity protective effects of Curcumin (CUR), whose anti-inflammatory effects are well known, have been expressed in the literature. In this study, we assumed that methotrexate-induced oxidative stress and proinflammatory response can be suppressed with curcumin treatment. This study was planned to investigate the protective role of curcumin against methotrexate-induced cytotoxicity and oxidative stress. In this study, mouse kidney cortical collection duct cells (mpkCCDc14) were used to investigate methotrexate-induced renal toxicity and subsequent molecular events in-vitro. The groups were designed as Control, CUR (10 μM and 24 hours), MET (5 μM and 24 hours) and MET+CUR. MET-induced oxidative stress was evaluated by determining mitochondrial membrane depolarization (MMD), cytosolic reactive oxygen species (ROS) production, apoptosis and caspase-3, caspase-9 activation levels in mpkCCDc14 cells. Although MET caused intracellular oxidative stress increase, this has been reduced by curcumin. Curcumin therapy regulated mitochondrial dysfunction and suppressed ROS formation in cells. Apoptosis, caspase-3 and caspase-9 activities have been increased in MET exposed cells. However, this condition was modulated by CUR therapy. As the result, MET-induced oxidative stress strengthens the role of mpkCCDc14 cells in the progression of chronic kidney disease, by leading to cell damage and creating a proinflammatory response. Curcumin can be an adjunctive therapy against methotrexate-induced cytosolic toxicity by antioxidant, anti-inflammatory and anti-apoptotic effects.

Keywords

Apoptosis, Curcumin, Cytotoxicity, Methotrexate

References

• Anand, P., Kunnumakkara, A.B., Newman, R.A., Aggarwal, B.B. 2007. Bioavailability of curcumin: problems and promises. Mol. Pharm. 4 (6), 807-818.
• Asvadi, I., Hajipour, B., Asvadi, A., Asl, N.A., Roshangar, L.,Khodadadi, A. 2011. Protective effect of pentoxyfilline in renaltoxicity after methotrexate administration. European Reviewfor Medical and Pharmacological Sciences 15, 1003–1009.
• Atessahin, A., Yilmaz, S., Karahan, I., Ceribasi, A.O., Karaoglu, A. 2005. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 212 (2), 116-123.
• Babiak, R.M., Campello, A.P., Carnieri, E.G., Oliveira, M.B. 1998. Methotrexate: pentose cycle and oxidative stress. CellBiochemistry and Function 16, 283–293.
• Balasubramanayam, M., Adaikala Koteswari, A., Sampath Kumar, R., Finny Monickaraj, S., Uma Maheswari, J., Mohan, V. 2003. Curcumin-induced inhibition of cellular reactive oxygen species generation: novel therapeutic implications. J. Biosci. 28 (6), 715-721.
• Biswas, S.K., McClure, D., Jimenez, L.A., Megson, I.L., Rahman, I. 2005. Curcumin induces glutathione biosynthesis and inhibits NF-kB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxidants redox Signal. 7 (1-2), 32-41.
• Choudhury, R.C., Ghosh, S.K., Palo, A.K. 2000. Cytogenetic toxicity of methotrexate in mouse bone marrow. Environ. Toxicol. Pharmacol. 8 (3), 191-196.
• Corona-Rivera, A., Urbina-Cano, P., Bobadilla-Morales, L., et al. 2007. Protective in vivo effect of curcumin on copper genotoxicity evaluated by comet and micronucleus assays. J. Appl. Genet. 48 (4), 389-396.
• El-Sheikh AA, Morsy MA, Abdalla AM, Hamouda AH, Alhaider IA. 2015 Mechanisms of thymoquinone hepatorenal protection in methotrexateinduced toxicity in rats. Mediators Inflamm. 1–12.
• Farruggio S, Cocomazzi G, Marotta P, Romito R, Surico D, Calamita G, Bellan M, Pirisi M, Grossini E. Genistein and 17β-Estradiol Protect Hepatocytes from Fatty Degeneration by Mechanisms Involving Mitochondria, Inflammasome and Kinases Activation. Cell Physiol Biochem. 2020 Apr 25;54(3):401-416.
• Fiorillo, C., Becatti, M., Pensafini, A., Cecchi, C., Lanzilao, L., Donzelli, G., Nassi, N.,Giannini, L., Borchi, E., Nassi, P. 2008. Curcumin protects cardiac cells against ischemia-reperfusion injury: effects on oxidative stress, NF-kB, and JNK pathways. Free Radic. Biol. Med. 45, 839.
• Huang B, Liu J, Fu S, Zhang Y, Li Y, He D, Ran X, Yan X, Du J, Meng T, Gao X, Liu D. α-Cyperone Attenuates H(2)O(2)-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2. Front Pharmacol. 2020 Apr 8;11:281.
• Huang, C.F., Cui, X.Q., Yang, C.F., Wang, X.B., Xu, H., Sha, Y.Y., Niu, J.Z. 2011. Effects of curcumin on micronuclei formation and chromosome aberration induced by cyclophosphamide in mice. China J. Traditional Chin. Med. Pharm. 6, 042.
• Jordan, P., Carmo-Fonseca, M., 2000. Molecular mechanisms involved in cisplatin cytotoxicity. Cell. Mol. Life Sci. CMLS 57, 1229-1235.
• Joshi DC, Bakowska JC. 2011. Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J Vis Exp 51: 2704.
• Iwona PC, Monika GG, Dorota NC, Mariola H, Marcin S, Magdalena I, Agnieszka K, Jarosław D. 2020. Pioglitazone as a modulator of the chemoresistance of renal cell adenocarcinoma to methotrexate. Oncology Reports. 43(3) 1019-1030.
• Kawamori, T., Lubet, R., Steele, V.E., Kelloff, G.J., Kaskey, R.B., Rao, C.V., Reddy, B.S. 1999. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res. 59 (3), 597-601.
• Keil VC, Funke F, Zeug A, Schild D, Müller M. 2011. Ratiometric high-resolution imaging of JC-1 fluorescence reveals the subcellular heterogeneity of astrocytic mitochondria. Pflugers Arch. 462:693-708.
• Kliem C, Merling A, Giaisi M, Köhler R, Krammer PH, Li-Weber M. 2012. Curcumin suppresses T cell activation by blocking Ca2+ mobilization and nuclear factor of activated T cells (NFAT) activation. J Biol Chem. 287(13), 10200–10209.
• Liu F, Ni W, Zhang J, Wang G, Li F, Ren W. 2017. Administration of curcumin protects kidney tubules against renal ischemia-reperfusion injury (RIRI) by modulating nitric oxide (NO) signaling pathway. Cell Physiol Biochem. 44(1), 401–411.
• Menon, V.P., Sudheer, A.R. 2007. Antioxidant and anti-inflammatory properties of curcumin. In: The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Springer, US, pp. 105-125.
• Mandil R, Prakash A, Rahal A, Singh SP, Sharma D, Kumar R, Garg SK. In vitro and in vivo effects of flubendiamide and copper on cyto-genotoxicity, oxidative stress and spleen histology of rats and its modulation by resveratrol, catechin, curcumin and α-tocopherol. BMC Pharmacol Toxicol. 2020 Apr 23;21(1):29.
• Mora, L.D.O., Antunes, L.M.G., Francescato, H.D.C., Bianchi, M.D.L.P. 2003. The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats. Pharmacol. Res. 47 (6), 517-522.
• Mora, L.D.O., Antunes, L.M.G., Francescato, H.D.C., Bianchi, M.L.P. 2002. The effects of oral glutamine on cisplatin-induced genotoxicity in Wistar rat bone marrow cells. Mutat. Res. 518 (1), 65-70.
• Murray, M.T., Pizzorno, J.E. 1999. Curcuma longa (turmeric). In: Textbook of Natural Medicine. Churchill Livingstone, Inc., p. 689. Norris, I., Sriganth, P., Premalatha, B. 1999. Dietary curcumin with cisplatin administration modulates tumour marker indices in experimental fibrosarcoma. Pharmacol. Res. 39 (3), 175-179.
• Palipoch, S., Punsawad, C., Chinnapun, D., Suwannalert, P. 2014. Amelioration of cisplatin-induced nephrotoxicity in rats by curcumin and a-tocopherol. Trop. J. Pharm. Res. 12 (6), 973-979.
• Said Salem NI, Noshy MM, Said AA. 2017. Modulatory effect of curcumin against enotoxicity and oxidative stress induced by cisplatin and methotrexate in male mice. Food Chem Toxicol. Jul;105:370-376.
• Serpeloni, J.M., Almeida, M.R., Mercadante, A.Z., Bianchi, M.L.P., Antunes, L.M.G. 2013. Effects of lutein and chlorophyll b on GSH depletion and DNA damage induced by cisplatin in vivo. Hum. Exp. Toxicol. 32 (8), 828-836.
• Sreejayan, N., Rao, M.N. 1996. Free radical scavenging activity of curcuminoids. Arzneim. 46 (2), 169-171.
• Surh, Y.J., Chun, K.S. 2007. Cancer chemopreventive effects of curcumin. In: The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Springer, US, pp. 149-172.
• Tian, F., Fan, T., Zhang, Y., Jiang, Y., Zhang, X. 2012. Curcumin potentiates the antitumor effects of 5-FU in treatment of esophageal squamous carcinoma cells through downregulating the activation of NF-kB signaling pathway in vitro and in vivo. Acta biochimica biophysica Sinica 44 (10), 847-855.
• Tirkey, N., Kaur, G., Vij, G., Chopra, K. 2005. Curcumin, a diferuloylmethane, attenuates cyclosporine-induced renal dysfunction and oxidative stress in rat kidneys. BMC Pharmacol. 5 (1), 15.
• Tousson E, Atteya E, El-Atrash E, Jeweely O. I. 2014. Abrogation by Ginkgo Byloba leaf extract on hepatic and renal toxicity induced by methotrexate in rats. J Cancer Res Treat.2(3):44–51.
• Ureshino RP, Erustes AG, Bassani TB, Wachilewski P, Guarache GC, Nascimento AC, Costa AJ, Smaili SS, Pereira GJDS. 2019. The Interplay between Ca(2+) signaling pathways and neurodegeneration. Int J Mol Sci. 20(23): pii: E6004.
• Weijl, N.I., Elsendoorn, T.J., Lentjes, E.G.W.M., Hopman, G.D., Wipkink-Bakker, A., Zwinderman, A.H., et al. 2004. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur. J. Cancer 40 (11), 1713-1723.
• Widemann, B.C., Adamson, P.C. 2006. Understanding and managing methotrexate nephrotoxicity. Oncol. 11 (6), 694-703.
• Yao L, Yang L, Song H, Liu TG, Yan H. Silencing of lncRNA XIST suppresses proliferation and autophagy and enhances vincristine sensitivity in retinoblastoma cells by sponging miR-204-5p. Eur Rev Med Pharmacol Sci. 2020 Apr;24(7):3526-3537