Melatonin Supplementation Alleviates Free Radical Load, NF-?B, Cox-2 and IL-1?-Mediated Inflammatory Responses of the Liver of Cisplatin-treated Golden Hamster Mesocricetus auratus


Affiliations

  • Institute of Medical Sciences, Banaras Hindu University, Department of Biochemistry, Varanasi, Uttar Pradesh, 221005, India
  • Institute of Science, Banaras Hindu University, Department of Zoology, Varanasi, Uttar Pradesh, 221005, India

Abstract

Cisplatin is a chemotherapeutic drug which frequently induces hepato- and renal toxicities. Cisplatin-induced hepatic damage is an area less investigated compared to renal damage. In the present study we investigated the hepatic damage caused by cisplatin and its possible protection by the hormone melatonin. Adult male golden hamster Mesocricetus auratus (? 2 months of age, and ± 100 g bw) were randomly divided into four groups (n=5)- Group I- control (injected with normal saline), group II- cisplatin (single dose of 15 mg/kg bw, ip), group III- melatonin (100 ug/100 g bw ip for 4 days) and group IV- Mel pretreatment followed by cisplatin at the above-said doses. The animals were euthanized 48 hr after the last dose. Liver was dissected out for analysis (histology, antioxidant profile, NF-?B, IL-1?, Cox-2, Hemeoxygenase-I and Nrf2). Cisplatin treatment induced steatohepatitis-like changes in the liver, elevated TBARS and suppressed antioxidant profiles. Further, the expression of NF-?B, IL-1?, Cox-2, and Hemeoxygenase-I were increased and the expression of Nrf2 was decreased suggesting inflammatory damage to liver. Pre-treatment of melatonin reduced the cisplatin-mediated hepatic pro-oxidant/antioxidant balance and inflammatory responses. Therefore, melatonin pretreatment might be a supportive approach in cancer therapy as it negates some of the damaging effects of cisplatin on liver to an extent without interfering with its chemotherapeutic attributes.

Keywords

Cisplatin, Inflammation, Liver, Melatonin, Oxidative Damage

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References

Jamieson ER, Lippard SJ. Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev. 1999; 99:2467-2498. https://doi.org/10.1021/cr980421n. PMid: 11749487.

Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. 2003; 23:460-464. https://doi.org/10.1016/S0270-9295(03)00089-5.

Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatin-induced acute renal failure in the rat. Nephrol Dial Transpl. 1992; 7:1-7.

Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest. 2002; 110(6):835-842. https://doi.org/10.1172/JCI200215606. PMid:12235115 PMCid:PMC151130.

Shimeda Y, Hirotani Y, Akimoto Y, et al. Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats. Biol Pharmaceut Bullet. 2005; 28(9):1635-1638. https://doi.org/10.1248/bpb.28.1635. PMid:16141530.

Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad-spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002; 2:181-198. https://doi.org/10.2174/1568026023394443. PMid:11899100.

Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/ anticancer agent; cellular, biochemical and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002; 2:113-132. https://doi.org/10.2174/1568026023394407. PMid:11899096.

Treeck O, Halda, C, Ortmann O. Antiestrogens modulate MT1 melatonin receptor expression in breast and ovarian cancer cell lines. Oncol Rep. 2006; 15: 231-235. https://doi.org/10.3892/or.15.1.231. PMid:16328061.

Rodriguez C, Martin V, Herera F, et al. Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells. Int J Mol Sci 2013; 14:6597-6613. https://doi.org/10.3390/ijms14046597. PMid:23528889 PMCid:PMC3645656.

Santoro R, Mori F, Marani M, et al. Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation. Carcinogenesis. 2013; 34:1051-1061. https://doi.org/10.1093/carcin/bgt025. PMid:23354312.

Ohkawa H, Ohishi N, Yagi K. Reaction of linoleic acid hydroperoxide with thiobarbituric acid. J Lip Res. 1978; 19:1053-1057. https://doi.org/10.1016/S0022-2275(20)406 90-X.

Das K, Samanta L, Chainy GBN. A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Indian J Biochem Biophys. 1999; 37:201-204.

Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972; 47:389-394. https://doi.org/10.1016/0003-2697(72) 90132-7.

Goswami S, Haldar C. UVB irradiation severely induces systemic tissue injury by augmenting oxidative load in a tropical rodent: Efficacy of melatonin as an antioxidant. J Photochem Photobiol. B. 2014; 141:84-92. https://doi.org/10.1016/j.jphotobiol.2014.08.027. PMid:25463654.

Sahin K, Tuzcu M, Gencoglu H, et al. Epigallocatechin- 3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci. 2010; 87:240-245. https://doi.org/10.1016/j.lfs.2010.06.014. PMid:20619277.

Kilic U, Kilic E, Tuzcu Z, et al. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/ HO-1 pathway. Nutri Metabol. 2013; 10:1-8. https://doi.org/10.1186/1743-7075-10-7. PMid:23311701 PMCid:PMC3561216.

Palipoch S, Punsawad C, Biochemical and histological study of rat liver and kidney injury induced by Cisplatin. J Toxicol Pathol. 2013; 26:293-299 https://doi.org/10.1293/tox.26.293. PMid:24155562 PMCid:PMC3787607.

I?eri S, Ercan F, Gedik N, et al. Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology 2007; 230:256-264. https://doi.org/10.1016/j.tox.2006.11.073. PMid:17196726.

Zeki Y, Sogut S, Odaci E, et al. Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats. Pharmacol Res. 2003; 47:149-156. https://doi.org/10.1016/S1043-6618(02)00282-7.

Martins NM, Santos NAG, Curti C, et al. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J Appl Toxicol. 2008; 28:337-344. https://doi.org/10.1002/jat.1284.PMid:17604343.

Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates cisplatin induced renal injury: Importance of superoxide. J Am Soc Nephrol. 2001; 12:2683-2690. https://doi.org/10.1681/ASN.V12122683. PMid:11729237.

Rahman I, Biswas SK, Kirkham PA. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol. 2006; 72:1439-1452. https://doi.org/10.1016/j.bcp.2006.07.004. PMid:16920072.

Syed DN, Afaq F, Kweon MH, et al. Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene. 2007; 26(5):673-682. https://doi.org/10.1038/sj.onc.1209829. PMid:16862172.

Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trend Pharmacol Sci. 2003; 24(2):96-102. https://doi.org/10.1016/S0165-6147(02)00043-3.

Liu W, Reinmuth N, Stoeltzing O, et al. Cyclooxygenase-2 Is Up-Regulated by Interleukin-1? in Human Colorectal Cancer Cells via Multiple Signaling Pathways? Cancer Res. 2003; 63:3632-3636.

Farombi EO, Shrotriya S, Na HK, et al. Curcumin attenuates dimethylnitrosamine- induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food Chem Toxicol. 2008; 46(4):1279-1287. https://doi.org/10.1016/j.fct.2007.09.095.PMid:18006204.

Surh YJ, Na HK, NF-kappa B and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with antiinflammatory and antioxidant phytochemicals. Genes Nutr. 2008; 2:313-17. https://doi.org/10.1007/s12263-007-0063-0. PMid:18850223 PMCid: PMC2478481.

Thimmulappa RK, Lee H, Rangasamy T, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006; 116:984-995. https://doi.org/10.1172/JCI25790. PMid:16585964 PMCid:PMC1421348.

Molina-Holgado E, Ortiz S, Molina-Holgado F, Guaza C. Induction of COX-2 and PGE2 biosynthesis by IL-1b is mediated by PKC and mitogen-activated protein kinases in murine astrocytes. Br J Pharmacol. 2000; 131:152-159. https://doi.org/10.1038/sj.bjp.0703557. PMid:10960082 PMCid:PMC1572306.

Rehman MU, Ali N, Rashid S, et al., Alleviation of hepatic injury by chrysin in cisplatin administered rats: Probable role of oxidative and inflammatory markers. Pharmacol Rep. 2014; 66:1050-1059. https://doi.org/10.1016/j.pharep.2014.06.004. PMid:25443734.

Tan DX, Manchester LC, Reiter RJ, et al. Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. Free Rad Biol Med. 2000; 29:1177-1185. https://doi.org/10.1016/S0891-5849(00)00435-4.

Slominski A, Wortsman J, Tobin DJ. The cutaneous serotoninergic/melatoninergic system: Securing a place under the sun. FASEB J. 2005; 19:176-194. https://doi.org/10.1096/fj.04-2079rev. PMid:15677341.

Saretzki G, Petersen S, Petersen I, et al. hTERT gene dosage correlates with telomerase activity in human lung cancer cell lines. Cancer Lett. 2002; 176:81-91. https://doi.org/10.1016/S0304-3835(01)00644-9.

Lu JJ, Fu L, Tang Z, et al. Melatonin inhibits AP-2?/hTERT, NF-?B/COX-2 and Akt/ERK and activates caspase/Cyto C signaling to enhance the antitumor activity of berberine in lung cancer cells. Oncotarget. 2015; 7:2985-3001. https://doi.org/10.18632/oncotarget.6407. PMid:26672764 PMCid:PMC4823085.

Reiter RJ, Tan DX, Sainz RM. et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002; 54:1299-1321. https://doi.org/10.1211/002235702760345374. PMid:12396291.


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