Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Possible Protective Effects of Curcumin via Modulating of Androgen Receptor (AR) and Oct2 Gene Alterations in Cisplatin-Induced Testicular Toxicity in Rat

Author(s): Amin A. Fard*, Mahrokh Samadi and Abdolrahman Biabangard

Volume 21, Issue 3, 2021

Published on: 11 May, 2020

Page: [458 - 463] Pages: 6

DOI: 10.2174/1871530320666200511073302

Price: $65

Abstract

Background: Cisplatin is a chemotherapeutic drug used to treat testicular cancer that induces testicular toxicity. This study aimed to investigate the possible role of androgens, androgen receptor, and organic cation transporter 2 (OCT2) in the protective effects of curcumin on cisplatininduced testicular toxicity.

Methods: Thirty male Wistar rats were divided into five groups: 1- control (normal saline, 0.5 ml ip, daily for 10 consecutive days); 2- cisplatin (10 mg/kg ip, single dose at the first day); 3- cisplatin + curcumin (10 mg/kg ip, dissolved in 5% DMSO, daily for 10 consecutive days); 4- cisplatin + vehicle (DMSO 5%, 0.3 ml ip); and 5- curcumin (10 mg/kg ip). At the end of the study, a blood sample was obtained for testosterone measurement. The left testis was kept at -80 to measure androgen receptor (AR) and type 2 organic cation transporter (OCT2) gene expression and the right testis were kept in 10% formalin for histological analysis.

Results: Cisplatin significantly decreased serum testosterone, declined testis AR gene expression, and increased OCT2 gene expression in testis (p<0.01). Curcumin treatment significantly prevented these alterations in testosterone and gene expressions (p<0.01). Moreover, curcumin significantly reversed the cisplatin-induced kidney tissue injury and increased spermatid and spermatozoa.

Conclusion: It is concluded that the ameliorative effect of curcumin in cisplatin-induced reproductive disorders was due to the modulation of testosterone and androgen receptors.

Keywords: Cisplatin, androgen receptors, organic cation transporter, curcumin, testis, OCT2 gene.

« Previous Next »
Graphical Abstract

[1]
Boulikas, T.; Vougiouka, M. Cisplatin and platinum drugs at the molecular level.(Review). Oncol. Rep., 2003, 10(6), 1663-1682.
[http://dx.doi.org/10.3892/or.10.6.1663] [PMID: 14534679]
[2]
Jordan, P.; Carmo-Fonseca, M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell. Mol. Life Sci., 2000, 57(8-9), 1229-1235.
[http://dx.doi.org/10.1007/PL00000762] [PMID: 11028915]
[3]
Hydrogen sulfide ameliorates the kidney dysfunction and damage in 9 cisplatin-induced nephrotoxicity in rat In: In: Ahangarpour, A.; Fard, A.A.; Gharibnaseri, M.K.; Jalali, T.; Rashidi, I., Eds.; Veterinary research forum; , 2014.
[4]
Silici, S.; Ekmekcioglu, O.; Eraslan, G.; Demirtas, A. Antioxidative effect of royal jelly in cisplatin-induced testes damage. Urology, 2009, 74(3), 545-551.
[http://dx.doi.org/10.1016/j.urology.2009.05.024] [PMID: 19616287]
[5]
Ateşşahin, A.; Şahna, E.; Türk, G.; Ceribaşi, A.O.; Yilmaz, S.; Yüce, A.; Bulmuş, O. Chemoprotective effect of melatonin against cisplatin-induced testicular toxicity in rats. J. Pineal Res., 2006, 41(1), 21-27.
[http://dx.doi.org/10.1111/j.1600-079X.2006.00327.x] [PMID: 16842537]
[6]
Aggarwal, B.B.; Sung, B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol. Sci., 2009, 30(2), 85-94.
[http://dx.doi.org/10.1016/j.tips.2008.11.002] [PMID: 19110321]
[7]
Noorafshan, A.; Karbalay-Doust, S.; Valizadeh, A.; Aliabadi, E. Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach. Exp. Toxicol. Pathol., 2011, 63(7-8), 627-633.
[http://dx.doi.org/10.1016/j.etp.2010.05.004] [PMID: 20627677]
[8]
Khorsandi, L.; Mirhoseini, M.; Mohamadpour, M.; Orazizadeh, M.; Khaghani, S. Effect of curcumin on dexamethasone-induced testicular toxicity in mice. Pharm. Biol., 2013, 51(2), 206-212.
[http://dx.doi.org/10.3109/13880209.2012.716854] [PMID: 23116244]
[9]
Aktas, C.; Kanter, M.; Erboga, M.; Ozturk, S. Anti-apoptotic effects of curcumin on cadmium-induced apoptosis in rat testes. Toxicol. Ind. Health, 2012, 28(2), 122-130.
[http://dx.doi.org/10.1177/0748233711407242] [PMID: 21632575]
[10]
Tousson, E.; Hafez, E.; Masoud, A.; Hassan, A.A. Abrogation by curcumin on testicular toxicity induced by cisplatin in rats. J. Cancer Res. Treat., 2014, 2(3), 64-68.
[http://dx.doi.org/ 10.12691/jcrt-2-3-4]
[11]
Ilbey, Y.O.; Ozbek, E.; Cekmen, M.; Simsek, A.; Otunctemur, A.; Somay, A. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum. Reprod., 2009, 24(7), 1717-1725.
[http://dx.doi.org/10.1093/humrep/dep058] [PMID: 19279034]
[12]
Heinlein, C.A.; Chang, C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol. Endocrinol., 2002, 16(10), 2181-2187.
[http://dx.doi.org/10.1210/me.2002-0070] [PMID: 12351684]
[13]
Lee, D.K.; Chang, C. Molecular communication between androgen receptor and general transcription machinery. J. Steroid Biochem. Mol. Biol., 2003, 84(1), 41-49.
[http://dx.doi.org/10.1016/S0960-0760(03)00005-0] [PMID: 12648523]
[14]
Hiort, O.; Holterhus, P.M. Androgen insensitivity and male infertility. Int. J. Androl., 2003, 26(1), 16-20.
[http://dx.doi.org/10.1046/j.1365-2605.2003.00369.x] [PMID: 12534933]
[15]
Bremner, W.J.; Millar, M.R.; Sharpe, R.M.; Saunders, P.T. Immunohistochemical localization of androgen receptors in the rat testis: evidence for stage-dependent expression and regulation by androgens. Endocrinology, 1994, 135(3), 1227-1234.
[http://dx.doi.org/10.1210/endo.135.3.8070367] [PMID: 8070367]
[16]
Woolveridge, I.; de Boer-Brouwer, M.; Taylor, M.F.; Teerds, K.J.; Wu, F.C.; Morris, I.D. Apoptosis in the rat spermatogenic epithelium following androgen withdrawal: changes in apoptosis-related genes. Biol. Reprod., 1999, 60(2), 461-470.
[http://dx.doi.org/10.1095/biolreprod60.2.461] [PMID: 9916015]
[17]
Kopalli, S.R.; Cha, K-M.; Jeong, M-S.; Lee, S-H.; Sung, J-H.; Seo, S-K.; Kim, S.K. Pectinase-treated Panax ginseng ameliorates hydrogen peroxide-induced oxidative stress in GC-2 sperm cells and modulates testicular gene expression in aged rats. J. Ginseng Res., 2016, 40(2), 185-195.
[http://dx.doi.org/10.1016/j.jgr.2015.08.005] [PMID: 27158240]
[18]
Kopalli, S.R.; Won, Y-J.; Hwang, S-Y.; Cha, K-M.; Kim, S-Y.; Han, C-K. Korean Red Ginseng protects against doxorubicin-induced testicular damage: an experimental study in rats. J. Funct. Foods, 2016, 20, 96-107.
[http://dx.doi.org/10.1016/j.jff.2015.10.020]
[19]
Wang, H-j.; Feng, L.; Chu, Z.; Yu, N.; Yang, Q.; Zhang, Z-q. Study on the changes of rat testis androgen receptor mRNA expression and plasma testosterone after cold stress. Lishizhen Med. Mater. Med. Res., 2008, 4, 929-930.
[20]
Xiong, X.; Wang, A.; Liu, G.; Liu, H.; Wang, C.; Xia, T.; Chen, X.; Yang, K. Effects of p,p′-dichlorodiphenyldichloroethylene on the expressions of transferrin and androgen-binding protein in rat Sertoli cells. Environ. Res., 2006, 101(3), 334-339.
[http://dx.doi.org/10.1016/j.envres.2005.11.003] [PMID: 16380112]
[21]
Tsui, K.H.; Feng, T.H.; Lin, C.M.; Chang, P.L.; Juang, H.H. Curcumin blocks the activation of androgen and interlukin-6 on prostate-specific antigen expression in human prostatic carcinoma cells. J. Androl., 2008, 29(6), 661-668.
[http://dx.doi.org/10.2164/jandrol.108.004911] [PMID: 18676361]
[22]
Nakamura, K.; Yasunaga, Y.; Segawa, T.; Ko, D.; Moul, J.W.; Srivastava, S.; Rhim, J.S. Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines. Int. J. Oncol., 2002, 21(4), 825-830.
[http://dx.doi.org/10.3892/ijo.21.4.825] [PMID: 12239622]
[23]
Shi, Q.; Shih, C-Y.; Lee, K. Novel anti-prostate cancer curcumin analogues that enhance androgen receptor degradation activity. Anticancer. Agents Med. Chem., 2009, 9(8), 904-912.
[http://dx.doi.org/10.2174/187152009789124655]
[24]
Augustine, L.M.; Markelewicz, R.J., Jr; Boekelheide, K.; Cherrington, N.J. Xenobiotic and endobiotic transporter mRNA expression in the blood-testis barrier. Drug Metab. Dispos., 2005, 33(1), 182-189.
[http://dx.doi.org/10.1124/dmd.104.001024] [PMID: 15494472]
[25]
Klein, D.M.; Cherrington, N.J. Organic and inorganic transporters of the testis: A review. Spermatogenesis, 2015, 4(2)e979653
[http://dx.doi.org/10.4161/21565562.2014.979653] [PMID: 26413398]
[26]
Maeda, T.; Goto, A.; Kobayashi, D.; Tamai, I. Transport of organic cations across the blood-testis barrier. Mol. Pharm., 2007, 4(4), 600-607.
[http://dx.doi.org/10.1021/mp070023l] [PMID: 17616214]
[27]
Jung, N.; Lehmann, C.; Rubbert, A.; Knispel, M.; Hartmann, P.; van Lunzen, J.; Stellbrink, H.J.; Faetkenheuer, G.; Taubert, D. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab. Dispos., 2008, 36(8), 1616-1623.
[http://dx.doi.org/10.1124/dmd.108.020826] [PMID: 18490433]
[28]
Sawhney, P.; Giammona, C.J.; Meistrich, M.L.; Richburg, J.H. Cisplatin-induced long-term failure of spermatogenesis in adult C57/Bl/6J mice. J. Androl., 2005, 26(1), 136-145.
[PMID: 15611578]
[29]
Cherry, S.M.; Hunt, P.A.; Hassold, T.J. Cisplatin disrupts mammalian spermatogenesis, but does not affect recombination or chromosome segregation. Mutat. Res., 2004, 564(2), 115-128.
[http://dx.doi.org/10.1016/j.mrgentox.2004.08.010] [PMID: 15507376]
[30]
Ishikawa, T.; Kamidono, S.; Fujisawa, M. Fertility after high-dose chemotherapy for testicular cancer. Urology, 2004, 63(1), 137-140.
[http://dx.doi.org/10.1016/j.urology.2003.08.029] [PMID: 14751366]
[31]
Beytur, A.; Ciftci, O.; Oguz, F.; Oguzturk, H.; Yilmaz, F. Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. Cancer Chemother. Pharmacol., 2012, 69(1), 207-213.
[http://dx.doi.org/10.1007/s00280-011-1692-y] [PMID: 21681572]
[32]
Türk, G.; Ateşşahin, A.; Sönmez, M.; Ceribaşi, A.O.; Yüce, A. Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil. Steril., 2008, 89(5)(Suppl.), 1474-1481.
[http://dx.doi.org/10.1016/j.fertnstert.2007.04.059] [PMID: 17681317]
[33]
Sisci, D.; Panno, M.L.; Salerno, M.; Maggiolini, M.; Pezzi, V.; Morrone, E.G.; Mauro, L.; Aquila, S.; Marsico, S.; Lanzino, M.; Andò, S. A time course study on the “in vitro” effects of T3 and testosterone on androgen and estrogen receptors in peripuberal primary rat Sertoli cells. Exp. Clin. Endocrinol. Diabetes, 1997, 105(4), 218-224.
[http://dx.doi.org/10.1055/s-0029-1211755] [PMID: 9285209]
[34]
Arambepola, N.K.; Bunick, D.; Cooke, P.S. Thyroid hormone effects on androgen receptor messenger RNA expression in rat Sertoli and peritubular cells. J. Endocrinol., 1998, 156(1), 43-50.
[http://dx.doi.org/10.1677/joe.0.1560043] [PMID: 9496232]
[35]
Ree, A.H.; Hansson, V.; Walaas, S.I.; Eskild, W.; Taskén, K.A. Calcium/phospholipid-dependent protein kinases in rat Sertoli cells: regulation of androgen receptor messenger ribonucleic acid. Biol. Reprod., 1999, 60(5), 1257-1262.
[http://dx.doi.org/10.1095/biolreprod60.5.1257] [PMID: 10208993]
[36]
McPhaul, M.J. Androgen receptor mutations and androgen insensitivity. Mol. Cell. Endocrinol., 2002, 198(1-2), 61-67.
[http://dx.doi.org/10.1016/S0303-7207(02)00369-6] [PMID: 12573815]
[37]
Miniero, R.; Saracco, P.; Pastore, G.; Zurlo, M.G.; Terracini, B.; Rosso, P.; Masera, G. Italian association of pediatric hematology-oncology (AIEOP). Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Med. Pediatr. Oncol., 1995, 24(2), 71-76.
[http://dx.doi.org/10.1002/mpo.2950240202] [PMID: 7990766]
[38]
Schinkel, A.H.; Smit, J.J.; van Tellingen, O.; Beijnen, J.H.; Wagenaar, E.; van Deemter, L.; Mol, C.A.; van der Valk, M.A.; Robanus-Maandag, E.C.; te Riele, H.P. Disruption of the mouse mdr1a Pglycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell, 1994, 77(4), 491-502..
[http://dx.doi.org/10.1016/0092-8674(94)90212-7 ] [PMID: 7910522]

Rights & Permissions Print Cite
Article Metrics
22
1
© 2024 Bentham Science Publishers | Privacy Policy