Abstract
Anti-cancer drugs such as cisplatin and doxorubicin are effectively used more than radiotherapy. Cisplatin is a chemotherapeutic drug, used for treatment of various forms of cancer. However, it has side effects such as ototoxicity and nephrotoxicity. Cisplatin-induced nephrotoxicity increases tubular damage and renal dysfunction. Consequently, we investigated the beneficial effect of cynaroside on cisplatin-induced kidney injury using HK-2 cell (human proximal tubule cell line) and an animal model. Results indicated that 10 µM cynaroside diminished cisplatin-induced apoptosis, mitochondrial dysfunction and caspase-3 activation, cisplatin-induced upregulation of caspase-3/MST-1 pathway decreased by treatment of cynaroside in HK-2 cells. To confirm the effect of cynaroside on cisplatin-induced kidney injury in vivo, we used cisplatin exposure animal model (20 mg/kg, balb/c mice, i.p., once a day for 3 days). Renal dysfunction, tubular damage and neutrophilia induced by cisplatin injection were decreased by cynaroside (10 mg/kg, i.p., once a day for 3 days). Results indicated that cynaroside decreased cisplatin-induced kidney injury in vitro and in vivo, and it could be used for improving cisplatin-induced side effects. However, further experiments are required regarding toxicity by high dose cynaroside and caspase-3/ MST-1-linked signal transduction in the animal model.
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Park, J.C., Park, J.G., Kim, H.J., Hur, J.M., Lee, J.H., Sung, N.J., Chung, S.K. and Choi, J.W. (2002) Effects of extract from Angelica keiskei and its component, cynaroside, on the hepatic bromobenzene-metabolizing enzyme system in rats. Phytother. Res., 16, S24–S27.
Sun, X., Sun, S.G., Wang, M., Xiao, J. and Sun, X.B. (2011) Protective effects of cynaroside against H2O2-induced apoptosis in H9c2 cardiomyoblasts. J. Cell Biochem., 112, 2019–2029.
Wen, H.U., Ting, G., Jiang, W.J., Dong, G.L., Chen, D.W., Yang, S.L. and Li, H.R. (2015) Effects of ultrahigh pressure extraction on yield and antioxidant activity of chlorogenic acid and cynaroside extracted from flowe bubs of Lonicera japonica. Chin. J. Nat. Med., 13, 445–453.
Lin, L.C., Pai, Y.F. and Tsai, T.H. (2015) Isolation of luteolin and luteolin-7-O-glucoside from Dendranthema morifolium Ramat Tzvel and pharmacokinetics in rat. J. Agric. Food Chem., 9, 7700–7706.
Kang, K.J. and Lee, J.H. (2010) Characteristics of gastric cancer in Korea-with an emphasis on the increase of the early gastric cancer (EGC). J. Korean Med. Assoc., 53, 283–289.
Kang, K.P., Kim, D.H., Jung, Y.J., Lee, A.S., Lee, S., Lee, S.Y., Jang, K.Y., Sung, M.J., Park, S.K. and Kim W. (2009) Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol. Dial. Transplant., 24, 3012–3020.
Kolb, R., Ghazi, M. and Barfuss, D. (2003) Inhibition of basolateral transport and cellular accumulation of cDDP and N-acetyl-L-cysteine-cDDP by TEA and PAH in the renal proximal tubule. Cancer. Chemother. Pharmacol., 51, 132–138.
Ronald, P.M., Raghu. K.T., Ganesan, R. and William, B.R. (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel), 2, 2490–2518.
Yao, X., Panichpisal, K., Kurtzman, M. and Nugent, K. (2007) Cisplatin nephrotoxicity: a review. Am. J. Med. Sci., 334, 115–154.
Ling, P., Lu, T.J., Yuan, C.J. and Lai, M.D. (2008) Biosignaling of mammalian Ste20-related kinases. Cell. Signal., 20, 1237–1247.
Qin, F., Tian, J., Zhou, D. and Chen, L. (2013) Mst1 and Mst2 kinases: regulations and disease. Cell. Biosci., 3, 31.
Meng, Z., Moroishi, T. and Guan, K.L. (2016) Mechanisms of hippo pathway regulation. Genes Dev., 30, 1–17.
Amin, A., Federico, P., Zahra, A., Supreet, K., Vrushali, K., Ting, Y., Thomas, F., Wufan, T., Jose, O., Francois, P., Julie, K.C. and Kathrin, M. (2014) MST-1 is a novel regulator of apoptosis in pancreatic beta-cells. Nat. Med., 20, 385–397.
Caretha, L.C. and Jonathan, C. (1995) Cloning and characterization of a human protein kinase with homology to Ste20. J. Biol. Chem., 270, 21695–21700.
Parham, M., Inti, Z., Kristi, B., Luigi, T., Luigi, T., Jeremy, R.J. and Alessandro, L. (2007) Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod. Pathol., 20, 331–338.
Faunel, S., Lewis, E.C., Reznikov, L., Koke, T.S., Somerset, H., Oh, D.J., Li, L., Klein, C.L., Dinarello, C.A. and Edelstein, C.L. (2007) Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. J. Phamacol. Exp. Ther., 322, 8–15.
Ozkok, A. and Edelstein, C.L. (2014) Pathophysiology of cisplatin-induced acute kidney injury. Biomed. Res. Int., 2014, 967826.
Oh, G.S., Kim, H.J., Shen, A.H., Lee, S.B., Khadka, D., Pandit, A. and So, H.S. (2014) Cisplatin-induced kidney dysfunction and perspectives on improving treatment strategies. Electrolyte Blood Press, 12, 55–65.
Yuna, F., Xie, Q., Wu, J., Bai, Y., Mao, B., Dong, Y., Bi, W., Ji, G., Tao, W., Wang, Y. and Yuan, Z. (2011) MST-1 promotes apoptosis through regulating sirt1-dependent p53 deacetylation. J. Biol. Chem., 286, 6940–6945.
Xu, C., Liu, C., Huang, W., Tu, S. and Wan, F. (2013) Effect of mst1 overexpression on the growth of human hepatocellular carcinoma HepG2 cells and the sensitivity to cisplatin in vitro. Acta Biochim. Biophys. Sin. (Shanghai), 45, 268–279.
Ura, S., Masuyama, M., Graves, J.D. and Gotoh, Y. (2001) MST1-JNK promotes apoptosis via caspase-dependent and independent pathways. Genes Cells, 6, 519–530.
Maejima, Y., Kyoi, S., Zhai, P., Liu, T., Li, H., Lvessa, A., Sciarretta, S., Del Re, D.P., Zablocki, D.K., Hsu, C.P., Lim, D.S., Isobe, M. and Sadoshima, J. (2013) Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat. Med., 19, 1478–1488.
Luo, X., Li, Z., Yan, Q., Li, X., Tao, D., Wang, J., Leng, Y., Gardner, K., Judge, S., Li, Q., Hu, J. and Gong, J. (2010) The human WW45 protein enhances MST-1 mediated apoptosis in vivo. Int. J. Mol. Med., 23, 357–362.
Hosseinian, S., Rad, A.K., Hadjzadeh, M.A.R., Roshan, N.M., Havakhah, S. and Shafiee, S. (2016) The protective effect of Nigella sativa against cisplatin-induced nephrotoxicity in rats. Avicenna J. Phytomed., 6, 44–54.
Bami, E., Ozakpinar, O.B., Ozdemir-Kumral, Z.N., Koroglu, K., Ercan, F., Cirakli, Z., Sekerler, T., Izzettin, F.V., Sancar, M. and Okuyan, B. (2017) Protective effect of ferulic acid on cisplatin induced nephrotoxicity in rats. Environ. Toxicol. Pharmacol., 54, 105–111.
Lou, X.Y., Cheng, J.L. and Zhang, B. (2015) Therapeutic effect and mechanism of breviscapine on cisplatin-induced nephrotoxicity in mice. Asian. Pac. J. Trop. Med., 8, 873–877.
Yin, X., Apostolov, E.O., Shah, S.V., Wang, X., Bogdanov, K.V., Buzder, T., Stewart, A.G. and Basnakian, A.G. (2007) Induction of renal endonuclease G by cisplatin is reduced in DNase I-deficient mice. J. Am. Soc. Nephrol., 18, 2544–2553.
Basnakian, A.G., Apostolov, E.O., Yin, X., Napirei, M., Mannherz, H.G. and Shah, S.V. (2005) Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. J. Am. Soc. Nephrol., 16, 697–702.
Hua, Z.J. and Xu, M. (2000) DNA fragmentation in apoptosis. Cell Res., 10, 205–211.
Khodarev, N.N., Sokolova, I.A. and Vaughan, A.T. (1998) Mechanisms of induction of apoptotic DNA fragmentation. Int. J. Radiat. Biol., 73, 455–467.
Jang, Y.J., Won, J.H., Back, M.J., Fu, Z., Jang, J.M., Ha, H.C., Hong, S.B., Chang, M. and Kim, D.K. (2017) Paraquat induces apoptosis through a mitochondria-dependent pathway in RAW 264.7 cells. Biomol. Ther. (Seoul), 23, 407–413.
Kroemer, G. and Reed, J.C. (2000) Mitochondrial control of cell death. Nat. Med., 6, 513–519.
Wadia, J.S., Chalmers-Redman, R.M.E., Ju, W.J.H., Carlile, G.W., Philips, J.L., Fraser, A,D. and Tatton, W.G. (1998) Mitochondrial membrane potential and nuclear changes in apoptosis acused by serum and nerve growth factor withdrawal: time course and modification by (-)-deprenyl. J. Neurosci., 18, 932–947.
Tadagavadi, R. and Reeves, W.B. (2017) Neutrophils in cisplatin AKI-mediator or marker? Kidney Int., 92, 11–13.
Ma, P., Zhang, S., Su, G., Qiu, G. and Wu, Z. (2015) Protective effects of icariin on cisplatin-induced acute renal injury in mice. Am. J. Transl. Res., 7, 2105–2114.
Park, C.M. and Song, Y.S. (2013) Luteolin and luteolin-7-O-glucoside inhibit lipopolysaccharide-induced inflammatory responses through modulation of NF-κB/AP-1/PI3K-Akt signaling cascades in RAW 264.7 cells. Nutr. Res. Pract., 7, 423–429.
Hwang, Y.J., Lee, E.J., Kim, H.R. and Hwang, K.A. (2013) Molecular mechanisms of luteolin-7-O-glucoside-induced growth inhibition on human liver cancer cells: G2/M cell cycle arrest and caspase-independent apoptotic signaling pathways. BMB Rep., 46, 611–616.
Yao, H., Shang, Z., Wang, P., Li, S., Zhang, Q., Tian, H., Ren, D. and Han, X. (2016) Protection of luteolin-7-O-glu-coside against doxorubicin-induced injury through PTEN/ Akt and ERK pathway in H9c2 cells. Cardiovasc. Toxicol., 16, 101–110.
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Nho, JH., Jung, HK., Lee, MJ. et al. Beneficial Effects of Cynaroside on Cisplatin-Induced Kidney Injury In Vitro and In Vivo . Toxicol Res. 34, 133–141 (2018). https://doi.org/10.5487/TR.2018.34.2.133
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DOI: https://doi.org/10.5487/TR.2018.34.2.133