Abstract
Cisplatin (CP) is commonly used in the treatment of various solid tumors. Its use, however, is hampered by nephrotoxicity. In this study, we compared the effect of betaine and melatonin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in mice. CP (20 mg/kg, given intraperitoneally on the 8th day of 12 days of the experiment) showed the typical physiological, biochemical, and histologic features of nephrotoxicity. CP-treated mice showed a significant reduction in food intake, body weight, and urine and fecal output. It also induced significant increases in the plasma concentrations of urea, creatinine, uric acid, phosphorous, adiponectin, interleukin-1β, interleukin-6, transforming growth factor -β1, tumor necrosis factor-α, and cystatin C. All these effects were significantly reduced by daily administration of betaine or melatonin at oral doses of 200 mg/kg and 10 mg/kg, respectively. Furthermore, using the two agents in combination caused further significant reductions in the above parameters. These findings suggest that betaine and melatonin concomitant use is likely to provide greater protection against CP-induced nephrotoxicity than when they are given singly, rendering them potentially suitable and safe agents to use in clinical trials to assess their possible beneficial actions in cancer patients receiving CP.
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References
Ali BH, Al Moundhri MS (2006) Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem Toxicol 44:1173–1183. https://doi.org/10.1016/j.fct.2006.01.013
Ali BH, Abdelrahman A, Al Suleimani Y, Manoj P, Ali H, Nemmar A, Al Za’abi M, (2020a) Effect of concomitant treatment of curcumin and melatonin on cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother 131:110761. https://doi.org/10.1016/j.biopha.2020.110761
Ali BH, Al Salam S, Al Suleimani Y, Al Za’abi M, Ashique M, Manoj P, Sudhadevi M, Al Tobi M, Nemmar A (2020b) Ameliorative effect of sesamin in cisplatin-induced nephrotoxicity in rats by suppressing inflammation, oxidative/nitrosative stress, and cellular damage. Physiol Res 69(1):61–72. https://doi.org/10.33549/physiolres.934142
Al Za’abi M, Al Busaidi M, Yasin J, Schupp N, Nemmar A, Ali BH (2015) Development of a new model for the induction of chronic kidney disease via intraperitoneal adenine administration, and the effect of treatment with gum acacia thereon. Am J Transl Res 7:28–38
Al Za’abi M, Al Salam S, Al Suleimani Y, Manoj P, Nemmar A, Ali BH (2018) Gum acacia improves renal function and ameliorates systemic inflammation, oxidative and nitrosative stress in streptozotocin-induced diabetes in rats with adenine-induced chronic kidney disease. Cell Physiol Biochem 45:2293–2304. https://doi.org/10.1159/000488176
Al Za’abi M, Al Salam S, Al Suleimani Y, Ashique M, Manoj P, Nemmar A, Ali BH (2021) Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats. Naunyn Schmiedebergs Arch Pharmacol 394:249–259. https://doi.org/10.1007/s00210-020-01976-1
Armutcu F, Demircan K, Yildirim U, Namuslu M, Yagmurca M, Celik HT (2019) Hypoxia causes important changes of extracellular matrix biomarkers and ADAMTS proteinases in the adriamycininduced renal fibrosis model. Nephrology (carlton) 24:863–875
Bonmati-Carrion MA, Tomas-Loba A (2021) Melatonin and cancer: a polyhedral network where the source matters. Antioxidants (basel) 10:210. https://doi.org/10.3390/antiox10020210
Casanova AG, Hernández-Sánchez MT, López-Hernández FJ, Martínez-Salgado C, Prieto M, Vicente-Vicente L, Morales AI (2020) Systematic review and meta-analysis of the efficacy of clinically tested protectants of cisplatin nephrotoxicity. Eur J Clin Pharmacol 76:23–33. https://doi.org/10.1007/s00228-019-02771-5
Craig SA (2004) Betaine in human nutrition. Am J Clin Nutr 80:539–549. https://doi.org/10.1093/ajcn/80.3.539
Chai GS, Jiang X, Ni ZF, Ma ZW, Xie AJ, Cheng XS, Wang Q, Wang JZ, Liu GP (2013) Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. J Neurochem 124:388–396. https://doi.org/10.1111/jnc.12094
Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM (2020) Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules 10:1211. https://doi.org/10.3390/biom10091211
D’Angelo G, Chimenz R, Reiter RJ, Gitto E (2020) Use of melatonin in oxidative stress related neonatal diseases. Antioxidants (basel) 9:477. https://doi.org/10.3390/antiox9060477
Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. https://doi.org/10.1016/j.ejphar.2014.07.025
Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C (2008) Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr 87:424–430. https://doi.org/10.1093/ajcn/87.2.424
Dutta S, Saha S, Mahalanobish S, Sadhukhan P, Sil PC (2018) Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice. Food Chem Toxicol 118:303–316. https://doi.org/10.1016/j.fct.2018.05.032
Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R (2017) Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int J Endocrinol 2017:1835195. https://doi.org/10.1155/2017/1835195
Hagar H, Medany AE, Salam R, Medany GE, Nayal OA (2015) Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats. Exp Toxicol Pathol 67:133–141. https://doi.org/10.1016/j.etp.2014.11.001
Haghi-Aminjan H, Farhood B, Rahimifard M, Didari T, Baeeri M, Hassani S, Hosseini R, Abdollahi M (2018) The protective role of melatonin in chemotherapy-induced nephrotoxicity: a systematic review of non-clinical studies. Expert Opin Drug Metab Toxicol 14(9):937–950. https://doi.org/10.1080/17425255.2018.1513492
Hamroun A, Lenain R, Bigna JJ, Speyer E, Bui L, Chamley P, Pottier N, Cauffiez C, Dewaeles E, Dhalluin X, Scherpereel A, Hazzan M, Maanaoui M, Glowacki F (2019) Prevention of cisplatin-induced acute kidney injury: a systematic review and meta-analysis. Drugs 79:1567–1582. https://doi.org/10.1007/s40265-019-01182-1
Hara M, Yoshida M, Nishijima H, Yokosuka M, Iigo M, Ohtani-Kaneko R, Shimada A, Hasegawa T, Akama Y, Hirata K (2001) Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats. J Pineal Res 30:129–138
Hardeland R (2019) Aging, melatonin, and the pro- and anti-inflammatory networks. Int J Mol Sci 20:1223. https://doi.org/10.3390/ijms20051223
Hoek J, Bloemendal KM, van der Velden LA, van Diessen JN, van Werkhoven E, Klop WM, Tesselaar ME (2016) Nephrotoxicity as a dose-limiting factor in a high-dose cisplatin-based chemoradiotherapy regimen for head and neck carcinomas. Cancers (basel) 8:21. https://doi.org/10.3390/cancers8020021
Gascon-Barré M, Huet PM, Belgiorno J, Plourde V, Coulombe PA (1989) Estimation of collagen content of liver specimens. Variation among animals and among hepatic lobes in cirrhotic rats. J Histochem Cytochem 37:377–381. https://doi.org/10.1177/37.3.2465335
Ghartavol MM, Gholizadeh-Ghaleh Aziz S, Babaei G, Hossein Farjah G, Hassan Khadem Ansari M (2019) The protective impact of betaine on the tissue structure and renal function in isoproterenol-induced myocardial infarction in rat. Mol Genet Genomic Med 7:e00579
Ghosh S (2019) Cisplatin: the first metal based anticancer drug. Bioorg Chem 88:102925. https://doi.org/10.1016/j.bioorg.2019.102925
Kar F, Hacioglu C, Kacar S, Sahinturk V, Kanbak G (2019) Betaine suppresses cell proliferation by increasing oxidative stress-mediated apoptosis and inflammation in DU-145 human prostate cancer cell line. Cell Stress Chaperones 24:871–881. https://doi.org/10.1007/s12192-019-01022-x (Epub 2019 Jul 31)
Kharbanda KK, Rogers DD 2nd, Mailliard ME, Siford GL, Barak AJ, Beckenhauer HC, Sorrell MF, Tuma DJ (2005) Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine. Biochem Pharmacol 70:1883–1890. https://doi.org/10.1016/j.bcp.2005.09.021
Kilic U, Kilic E, Tuzcu Z, Tuzcu M, Ozercan IH, Yilmaz O, Sahin F, Sahin K (2013) Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab (lond) 10:7
Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan DX (2009) Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 15:43–50. https://doi.org/10.2119/molmed.2008.00117
Lever M, Slow S (2010) The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem 43:732–744. https://doi.org/10.1016/j.clinbiochem.2010.03.009
Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev 7:684–696
Liu YL, Pan Y, Wang X, Fan CY, Zhu Q, Li JM, Wang SJ, Kong LD (2014) Betaine reduces serum uric acid levels and improves kidney function in hyperuricemic mice. Planta Med 80:39–47. https://doi.org/10.1055/s-0033-1360127
López-De León A, Rojkind M (1985) A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections. J Histochem Cytochem 33:737–743. https://doi.org/10.1177/33.8.2410480
Manni ML, Czajka CA, Oury TD, Gilbert TW (2011) Extracellular matrix powder protects against bleomycin-induced pulmonary fibrosis. Tissue Eng Part A 17:2795–2804. https://doi.org/10.1089/ten.tea.2011.0023
Manohar S, Leung N (2018) Cisplatin nephrotoxicity: a review of the literature. J Nephrol 31:15–25. https://doi.org/10.1007/s40620-017-0392-z
McRae MP (2013) Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. J Chiropr Med 12:20–25. https://doi.org/10.1016/j.jcm.2012.11.001
Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of Cisplatin Nephrotoxicity Toxins (basel) 2:2490–2518. https://doi.org/10.3390/toxins2112490
Nemmar A, Yuvaraju P, Beegam S, Ali BH (2015) Betaine (N, N, N-trimethylglycine) averts photochemically-induced thrombosis in pial microvessels in vivo and platelet aggregation in vitro. Exp Biol Med (maywood) 240:955–960. https://doi.org/10.1177/1535370214564749
Nemmar A, Al-Salam S, Beegam S, Yuvaraju P, Oulhaj A, Ali BH (2017) Water-pipe smoke exposure-induced circulatory disturbances in mice, and the influence of betaine supplementation thereon. Cell Physiol Biochem 41:1098–1112. https://doi.org/10.1159/000464117
Ozkok A, Edelstein CL (2014) Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int 2014:967826. https://doi.org/10.1155/2014/967826.
Ozturk F, Ucar M, Ozturk IC, Vardi N, Batcioglu K (2003) Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats. Urology 62:353–356. https://doi.org/10.1016/s0090-4295(03)00255-3
Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007
Prasad KN (2004) Multiple dietary antioxidants enhance the efficacy of standard and experimental cancer therapies and decrease their toxicity. Integr Cancer Ther 3:310–322. https://doi.org/10.1177/1534735404270936
Samanta S (2020) Physiological and pharmacological perspectives of melatonin. Arch Physiol Biochem 10:1–22. https://doi.org/10.1080/13813455.2020.1770799
Servais A, Meas-Yedid V, Buchler M, Morelon E, Olivo-Marin JC, Lebranchu Y, Legendre C, Thervet E (2007) Quantification of interstitial fibrosis by image analysis on routine renal biopsy in patients receiving cyclosporine. Transplantation 84:1595–1601. https://doi.org/10.1097/01.tp.0000295749.50525.bd
Volarevic V, Djokovic B, Jankovic MG, Harrell R, Fellabaum C, Djonov V, Arsenijevic N (2019) Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 26:25
Youn J, Cho E, Lee JE (2019) Association of choline and betaine levels with cancer incidence and survival: a meta-analysis. Clin Nutr 38:100–109. https://doi.org/10.1016/j.clnu.2018.01.042
Zhao G, He F, Wu C, Li P, Li N, Deng J, Zhu G, Ren W, Peng Y (2018) Betaine in inflammation: mechanistic aspects and applications. Front Immunol 9:1070. https://doi.org/10.3389/fimmu.2018.01070
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We would like to thank Ms. Priyadarsini Manoj for the technical help and the staff of the SQU Small Animal House for looking after the animals.
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BA conceived and designed the project. MS conducted the experiments. HA contributed to histopathology work. BA and MZ contributed to the interpretation of data. MZ and BA wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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This research was approved by the Animal Research Ethics Committee of the Sultan Qaboos University (SQU/AEC/2019–20/11). Procedures involving animals and their care were carried out in conformity with international laws and policies (EEC Council directives 86/609, OJL 358, December 12, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publications No. 85–23, 1985).
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Al Za’abi, M., Ali, H., Al Sabahi, M. et al. The salutary action of melatonin and betaine, given singly or concomitantly, on cisplatin-induced nephrotoxicity in mice. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1693–1701 (2021). https://doi.org/10.1007/s00210-021-02097-z
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DOI: https://doi.org/10.1007/s00210-021-02097-z