Pantoprazole abrogated cisplatin-induced nephrotoxicity in mice via suppression of inflammation, apoptosis, and oxidative stress
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The current study was designed to evaluate the potential abatement effect of pantoprazole against cisplatin-induced nephrotoxicity and establishing the possible protective mechanisms. Thirty-two male mice were allocated for treatment with saline, single dose of cisplatin (10 mg/kg/i.p), pantoprazole (30 mg/kg/once daily) for 5 days or combination of pantoprazole and cisplatin for 5 days. Urine, blood, and both kidneys were collected for further evaluations. Pantoprazole significantly countermand cisplatin-induced disfigurement of renal histology, kidney weight to body weight ratio, serum levels of creatinine and urea, and microalbuminuria. Furthermore, pantoprazole mostly normalized cisplatin-induced distortion of renal levels of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10) and renal content of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase 3). In addition, pantoprazole significantly subsided cisplatin-induced distortion of renal lipid peroxidation marker (MDA), renal superoxide dismutase, and catalase activities and renal reduced glutathione content. This study provides an evidence for the protective utility of short-term pantoprazole against cisplatin-induced nephrotoxicity in mice. The protective mechanism of pantoprazole could be through diminution of cisplatin-induced inflammation, oxidative stress, and their subsequent apoptotic renal cell death via abatement of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase3).
KeywordsCisplatin Pantoprazole Nephrotoxicity Oxidative stress Inflammation Apoptosis
We are greatly thankful to both Prof. Adel Kholoussy (Professor of Pathology, Cairo University, Egypt) and Dr. Sayed Abdel Raheem (Associate professor of histology, Al-Azhar University, Egypt) for their contribution in the histopathological examination.
RI, MSE, and MHH conceived and designed research, provided the necessary tools and reagents, acquired and validated data. MSE and MHH provided the funding and drafted the manuscript. RI conducted most of the experiments. MSE performed the formal statically analysis. MHH reviewed, edited, and submitted the manuscript. All authors read and approved the manuscript.
The authors disclosed individual full financial support and funding for this study. The authors disclosed personal financial support from authors MSE and MHH.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in our study involving animals were in accordance with the ethical standards and guidelines from Ethics Committee of the Experimental Animal Care Society, Al-Azhar University, Cairo, Egypt, and Taibah University, Kingdom of Saudi Arabia. In addition, all applicable international and national, guidelines for the care, and use of animals were followed. The protocol approval number is phr._Med. Research_ Protective. Trial. Anticancer. Drugs. Organs. Toxicity. Mice. 0000007
- Abdelrahman AM, Al Suleimani Y, Shalaby A, Ashique M, Manoj P, Nemmar A, Ali BH (2019) Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on cisplatin-induced nephrotoxicity in mice. Naunyn Schmiedebergs Arch Pharmacol 392:45–53. https://doi.org/10.1007/s00210-018-1564-7 CrossRefPubMedGoogle Scholar
- Avnet S, Lemma S, Cortini M, Pellegrini P, Perut F, Zini N, Kusuzaki K, Chano T, Grisendi G, Dominici M, De Milito A, Baldini N (2016) Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance. Oncotarget 7:63408–63423. https://doi.org/10.18632/oncotarget.11503 CrossRefPubMedPubMedCentralGoogle Scholar
- Bancroft JSA (1996) Enzyme histochemistry: theory and practice of histological techniques. Churchill Livingstone, New YorkGoogle Scholar
- Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L (2013) The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology 2:e22058. https://doi.org/10.4161/onci.22058 CrossRefPubMedPubMedCentralGoogle Scholar
- Cai J, Kim TS, Jang JY, Kim J, Shin K, Lee SP, Choi EK, Kim SH, Park M, Kim JB, Kim YB (2014) In vitro and in vivo anti-helicobacter pylori activities of FEMY-R7 composed of fucoidan and evening primrose extract. Lab Anim Res 30:28–34. https://doi.org/10.5625/lar.2014.30.1.28 CrossRefPubMedPubMedCentralGoogle Scholar
- Casanova AG, Hernandez-Sanchez MT, Lopez-Hernandez FJ, Martinez-Salgado C, Prieto M, Vicente-Vicente L, Morales AI (2019) Systematic review and meta-analysis of the efficacy of clinically tested protectants of cisplatin nephrotoxicity. Eur J Clin Pharmacol:1–11. https://doi.org/10.1007/s00228-019-02771-5 CrossRefGoogle Scholar
- Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP (2012) Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1alpha/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 113:2474–2487. https://doi.org/10.1002/jcb.24122 CrossRefPubMedPubMedCentralGoogle Scholar
- de Jongh FE, Verweij J, Loos WJ, de Wit R, de Jonge MJ, Planting AS, Nooter K, Stoter G, Sparreboom A (2001) Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733–3739. https://doi.org/10.1200/jco.2001.19.17.3733 CrossRefPubMedGoogle Scholar
- de Jongh FE, van Veen RN, Veltman SJ, de Wit R, van der Burg ME, van den Bent MJ, Planting AS, Graveland WJ, Stoter G, Verweij J (2003) Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 88:1199–1206. https://doi.org/10.1038/sj.bjc.6600884 CrossRefPubMedPubMedCentralGoogle Scholar
- De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L, Nilsson A, Fais S (2007) Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 67:5408–5417. https://doi.org/10.1158/0008-5472.can-06-4095 CrossRefPubMedGoogle Scholar
- Dugbartey GJ, Peppone LJ, de Graaf IA (2016) An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures. Toxicology 371:58–66. https://doi.org/10.1016/j.tox.2016.10.001 CrossRefPubMedPubMedCentralGoogle Scholar
- Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon MS, Kaube H, Limmroth V, Thomale J (2007) Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci 27:9451–9457. https://doi.org/10.1523/jneurosci.0523-07.2007 CrossRefPubMedPubMedCentralGoogle Scholar
- Eklow L, Moldeus P, Orrenius S (1984) Oxidation of glutathione during hydroperoxide metabolism. A study using isolated hepatocytes and the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea. Eur J Biochem 138:459–463. https://doi.org/10.1111/j.1432-1033.1984.tb07938.x CrossRefPubMedGoogle Scholar
- Fox E, Levin K, Zhu Y, Segers B, Balamuth N, Womer R, Bagatell R, Balis F (2018) Pantoprazole, an inhibitor of the organic cation transporter 2, does not ameliorate cisplatin-related ototoxicity or nephrotoxicity in children and adolescents with newly diagnosed osteosarcoma treated with methotrexate, doxorubicin, and cisplatin. Oncologist 23:762–e779. https://doi.org/10.1634/theoncologist.2018-0037 CrossRefPubMedPubMedCentralGoogle Scholar
- Hassan MH, Bahashawan SA, Abdelghany TM, Abd-Allah GM, Ghobara MM (2015) Crocin abrogates carbon tetrachloride-induced renal toxicity in rats via modulation of metabolizing enzymes and diminution of oxidative stress, apoptosis, and inflammatory cytokines. J Biochem Mol Toxicol 29:330–339. https://doi.org/10.1002/jbt.21702 CrossRefPubMedGoogle Scholar
- Johnson DLH (1967) Isolation of liver or kidney mitochondria. In: Ronald WEM (ed) Methods enzymol. Academic Press, pp 94–96Google Scholar
- Karihtala P, Soini Y (2007) Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS 115:81–103. https://doi.org/10.1111/j.1600-0463.2007.apm_514.x CrossRefPubMedGoogle Scholar
- Lu Y, Wahl LM (2005) Oxidative stress augments the production of matrix metalloproteinase-1, cyclooxygenase-2, and prostaglandin E2 through enhancement of NF-kappa B activity in lipopolysaccharide-activated human primary monocytes. J Immunol 175:5423–5429. https://doi.org/10.4049/jimmunol.175.8.5423 CrossRefPubMedGoogle Scholar
- Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F, Federici C, Iessi E, Parmiani G, Arancia G, Belardelli F, Fais S (2004) Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 96:1702–1713. https://doi.org/10.1093/jnci/djh305 CrossRefPubMedGoogle Scholar
- Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x CrossRefPubMedGoogle Scholar
- Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144:281–292. https://doi.org/10.1083/jcb.144.2.281 CrossRefPubMedPubMedCentralGoogle Scholar
- Suliman FA, Khodeer DM, Ibrahiem A, Mehanna ET, El-Kherbetawy MK, Mohammad HMF, Zaitone SA, Moustafa YM (2018) Renoprotective effect of the isoflavonoid biochanin A against cisplatin induced acute kidney injury in mice: effect on inflammatory burden and p53 apoptosis. Int Immunopharmacol 61:8–19. https://doi.org/10.1016/j.intimp.2018.05.010 CrossRefPubMedGoogle Scholar
- Tan Q, Joshua AM, Saggar JK, Yu M, Wang M, Kanga N, Zhang JY, Chen X, Wouters BG, Tannock IF (2015) Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy. Br J Cancer 112:832–840. https://doi.org/10.1038/bjc.2015.17 CrossRefPubMedPubMedCentralGoogle Scholar
- Udelnow A, Kreyes A, Ellinger S, Landfester K, Walther P, Klapperstueck T, Wohlrab J, Henne-Bruns D, Knippschild U, Wurl P (2011) Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS One 6:e20143. https://doi.org/10.1371/journal.pone.0020143 CrossRefPubMedPubMedCentralGoogle Scholar