Oksaliplatin Kaynaklı Testis Hasarı Üzerine Likopenin Etkilerinin Araştırılması

Abstract

Oksaliplatin (Olp) ilerlemiş kolorektalkanserlerin tedavisinde yaygın olarak kullanılan bir ilaçtır. Diğer platin türevlerine göre oksaliplatin, sadece hafif bir hematolojik ve gastrointestinal toksisiteye neden olmaktadır. Domateslerde ve ürünlerindebulunan asiklik bir hidrokarbon karotenoidolan likopen (Lcp), güçlü bir antioksidandır ve hayvan modellerinde antikanser özellikleri gösterilmiştir. Bu çalışma sıçanlarda Lcp’nin Olp ile indüklenen testis toksisitesine karşı koruyucu etkilerini değerlendirmeyi amaçlamaktadır. Araştırmada erkek Sprague Dawley sıçanları kullanıldı ve 5 deney grubu oluşturuldu: 1-kontrol grubu, 2-Likopen (Lcp) uygulanan grup, 3-Oksaliplatin (Olp) uygulanan grup, 4-Oksaliplatin + likopen 2 mg/kg (Olp+Lcp2) uygulanan grup ve 5-oksaliplatin + likopen 4 mg/kg (Olp+Lcp4) uygulanan grup. 1 ve 2. günler ile 5 ve 6. günler likopen uygulamasından 30 dakika sonra oksaliplatin 4 mg/kg dozunda %5 dektrozda çözülerek i.p. olarak uygulandı. Doku malondialdehit (MDA), glutatyon (GSH) düzeyleri, glutatyon peroksidaz (GPx), süperoksit dismutaz (SOD) ve katalaz (KAT) aktiviteleri biyokimyasal olarak belirlendi. Testis dokusunda oksaliplatin grubunda MDA düzeyleri yükselirken, GSH, GPx, SOD ve Kat değerleri azaldı. Likopenin oksaliplatin ile uygulanan farklı dozları ise MDA düzeyini azaltırken, GSH, GPx, SOD ve KAT aktivitelerini artırdı. Bu çalışma ile oksaliplatin ile oluşturulan testis hasarına karşı likopenin koruyucu özelliğinin olduğu tespit edilmiştir.

Keywords

• Likopen
• oksaliplatin
• oksidatif Stres
• rat

Investigation Of The Effects Of Lycopene On Oxaliplatin-Induced Testicular Damage

Abstract

Oxaliplatin (Olp) is a drug widely used in the treatment of advanced colorectal cancers. Compared to other platinum derivatives, oxaliplatin causes only mild haematological and gastrointestinal toxicity. Lycopene (Lcp), an acyclic hydrocarbon carotenoid found in tomatoes and their products, is a potent antioxidant and has been shown to have anticancer properties in animal models. This study aims to evaluate the protective effects of Lcp against Olp-induced testicular toxicity in rats. Male Sprague Dawley rats were used in the study and 5 experimental groups were formed: 1-control group, 2-Lycopene (Lcp) administered group, 3-Oxaliplatin (Olp) administered group, 4-Oxaliplatin + lycopene 2 mg/kg (Olp+Lcp2) administered group. group and 5-oxaliplatin + lycopene 4 mg/kg (Olp+Lcp4) administered group. On days 1 and 2, and days 5 and 6, 30 minutes after lycopene administration, oxaliplatin is dissolved in 5% dextrose ata dose of 4 mg/kg and administered i.p. was applied as Tissue malondialdehyde (MDA), glutathione (GSH) levels, glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (Cat) activities were determined biochemically. While MDA levels increasedin testicular tissue in the oxaliplatin group, GSH, GPx, SOD and CAT values decreased. Different doses of lycopene administered with oxaliplatin decreased MDA levels and increased GSH, GPx, SOD and CAT activities. In this study, it was determined that lycopene has a protective feature against testicular damage induced by oxaliplatin.

Keywords

• Lycopene
• oxaliplatin
• oxidative Stress
• rat

References

1. 1.Aebi H., 1984. Catalase in vitro. Meth Enzymol, 105, 121-126.
2. 2.Albrahim T., Alonazi M.A., 2021. Lycopene corrects metabolic syndrome and liver injury induced by high fat diet in obese rats through antioxidant, anti-inflammatory, antifibrotic pathways. Biomed Pharmacother, 141, 111831.
3. 3.Aksu E.H., Kandemir F.M., Küçükler S., 2021.Ameliorative effect of hesperidin on streptozotocin‐diabetes mellitus‐induced testicular DNA damage and sperm quality degradation in Sprague–Dawley rats. JFood Biochem, 45, 10: e13938.
4. 4.AksuE.H., Kandemir, F.M., Küçükler, S., 2021. The effects of hesperidin on colistin‐induced reproductive damage, autophagy, and apoptosis by reducing oxidative stress. Andrologia, 53, e13900.
5. 5.Aboubakr M., Elshafae S.M., Abdelhiee E.Y., Fadl S.E., Soliman A., Abdelkader A., Abdeen A., 2021. Antioxidant and anti-inflammatory potential of thymoquinone and lycopene mitigate the chlorpyrifos-induced toxic neuropathy. Pharmaceuticals, 14, 940.
6. 6.Ateşşahin A., Şahna E., Türk G., Çeribaşi A.O., Yılmaz S., Yüce A., Bulmuş Ö., 2006. Chemoprotective effect of melatonin against cisplatin‐induced testicular toxicity in rats. J Pineal Res, 41, 21-27.
7. 7.Behranvand N., Nasri F., Zolfaghari Emameh R., Khani P., Hosseini A., Garssen J., Falak R., 2021. Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunol Immunother, 1-20.
8. 8.Cao C., Sun S., Li J., Song C., Meng Q., Shi B., Shan A., 2021. Lycopene modulates lipid metabolism in rats and their offspring under a high-fat diet. Food Funct,12, 8960-8975.

9. 9.Carvalho G.C., de Camargo B. A. F., de Araújo J. T. C., Chorilli M., 2021. Lycopene: From tomato to its nutraceutical use and its association with nanotechnology. Trends Food Sci Technol, 118, 447-458.
10. 10.Celik H., Kucukler S., Ozdemir S., Comakli S., Gur C., Kandemir F. M., Yardim A., 2020. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology, 80, 29-40.
11. 11.Dunn T, Schmoll H, Grünwald V, Bokemeyer V, Casper JJInd., 1997. Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines. Invest New Drugs,15: 109-14.
12. 12.Elsayed A., Elkomy A., Elkammar R., YoussefG., Abdelhiee E.Y., Abdo W., Aboubakr M., 2021. Synergistic protective effects of lycopene and N-acetylcysteine against cisplatin-induced hepatorenal toxicity in rats. Sci Rep, 11, 1-10.
13. 13.Famurewa A.C., Ekeleme‐Egedigwe C.A., Onwe C.S., Egedigwe U.O., Okoro C.O., Egedigwe U.J., Asogwa N.T., 2020. Ginger juice prevents cisplatin‐induced oxidative stress, endocrine imbalance and NO/iNOS/NF‐κB signalling via modulating testicular redox‐inflammatory mechanism in rats. Andrologia, 52, e13786.
14. 14.Guerra A.S., Hoyos C.G., Molina-Ramírez C., Velásquez-Cock J., Vélez L., Gañán P., Zuluaga R., 2021. Extraction and preservation of lycopene: A review of the advancements offered by the value chain of nanotechnology. Trends Food Sci Technol, 116, 1120-1140.
15. 15.Hellberg V, Wallin I, Eriksson S, Hernlund E, Jerremalm E, Berndtsson M, Eksborg S, Arnér S.J., Shoshan M, Ehrsson H, Laurell G., 2009. Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity. J Natl Cancer Inst, 101, 37-47.
16. 16.Holmes J, Stanko J, Varchenko M, Ding H, Madden VJ, Bagnell Cr, Wyrick SD, Chaney SG., 1998. Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. 46, 342-51.
17. 17.Jerremalm E, Wallin I, Yachnin J, Ehrsson HJEjops., 2006. Oxaliplatin degradation in the presence of important biological sulphur-containing compounds and plasma ultrafiltrate. Eur J Pharm Biopharm, 28, 278-83.
18. 18.Kandemir F.M., Caglayan C., Darendelioglu E., Kucukler S., İzol E., Kandemir Ö., 2021. Modulatory effects of carvacrol against cadmium-induced hepatotoxicity and nephrotoxicity by molecular targeting regulation. Life Sci, 277, 119610.
19. 19.Kandemir F.M., Yıldırım S., Kucukler S., Caglayan C., Darendelioğlu E., Dörtbudak M.B., 2020. Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach." Food Chem Toxicol, 138, 111190.
20. 20.Kawai Y., Nakao T., Kunimura N., Kohda Y., Gemba MJJops., 2006. Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. J Pharmacol Sci, 0601120013-13.
21. 21.Küçükler S., Çomaklı S., Özdemir S., Çağlayan C., Kandemir F. M., 2021. Hesperidin protects against the chlorpyrifos‐induced chronic hepato‐renal toxicity in rats associated with oxidative stress, inflammation, apoptosis, autophagy, and up‐regulation of PARP‐1/VEGF. Environ Toxicol, 36, 1600-1617.
22. 22.Lévi F., Metzger G., Massari C., Milano GJCp., 2000. Oxaliplatin. Drugs, 38, 1-21.
23. 23.Li N., Wu X., Zhuang W., Xia L., Chen Y., Wu C., Zhou Y., 2021. Tomato and lycopene and multiple health outcomes: Umbrella review. Food Chem, 343, 128396.
24. 24.Lowry O. H., Rosebrough N. J., Farr A. L., Randall R. J., 1951. Protein measurement with the Folin phenol reagent. J Biol Chem, 193, 265-275.
25. 25.Luo F.R., Wyrick S.D., Chaney S.G., 1999. Pharmacokinetics and biotransformations of oxaliplatin in comparison with ormaplatin following a single bolus intravenous injection in rats. Cancer Chemother Pharmacol, 44, 19-28.
26. 26.Mani S., Graham M.A., Bregman D.B., Ivy P., Chaney SG., 2002. Oxaliplatin: a review of evolving concepts. Cancer Invest, 20, 246-63.
27. 27.Matkovics B., 1988. Determination of enzyme activity in lipid peroxidation and glutathione pathways. Laboratoriumi Diagnosztika, 15, 248-250.
28. 28.Misset J., Chollet P., Vennin P., Laplaige P., Lucas V., Gamelin E., Laademet A., Otero J.,2001. Multicenter phase II—III study of oxaliplatin plus cyclophosphamide vs. cisplatin plus cyclophosphamide in chemonaive advanced ovarian cancer patients. Ann Oncol, 12, 1411-1415.
29. 29.Özdemir S., KucuklerS., Çomaklı S., Kandemir F. M., 2020. The protective effect of Morin against ifosfamide-induced acute liver injury in rats associated with the inhibition of DNA damage and apoptosis. Drug Chem Toxicol, 1-10.
30. 30.Placer Z.A., Cushman, L.L., Johnson B.C., 1966.Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem, 16, 359-364.
31. 31.Parvez S., Tabassum H., Banerjee B.D., Raisuddin S.J.B., 2008. Taurine prevents tamoxifen‐induced mitochondrial oxidative damage in mice. Basic Clin Pharmacol Toxicol, 102, 382-87.
32. 32.Rao A., Agarwal S.J., 1999. Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr Res Rev, 19, 305-23.
33. 33.Reddy PH, Beal M.F., 2005. Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res Rev, 49, 618-32.
34. 34.Rezvanfar M.A., Rezvanfar M.A., Shahverdi A.R., Ahmadi A., Baeeri M., Mohammadirad A., Abdollahi M., 2013. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles. Toxicol Appl Pharmacol, 266, 356-65.
35. 35.Sadek K., Abouzed T., Nasr S.J., 2015. Lycopene modulates cholinergic dysfunction, Bcl-2/Bax balance, and antioxidant enzymes gene transcripts in monosodium glutamate (E621) induced neurotoxicity in a rat model. Can J Physiol Pharmacol, 94, 394-401.
36. 36.Sandhir R., Mehrotra A., Kamboj S.S., 2010. Lycopene prevents 3-nitropropionic acid-induced mitochondrial oxidative stress and dysfunctions in nervous system. Neurochem Int, 57, 579-87.
37. 37.Sedlak J., Lindsay, R. H., 1968. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal. Biochem, 25, 192-205.
38. 38.Sun Y. I., Oberley L. W., Li Y., 1988. A simple method for clinical assay of superoxide dismutase. Clin Chem, 34, 497-500.
39. 39.Tapiero H., Townsend D., Tew K.J.B., Pharmacotherapy., 2004. The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother, 58, 100-10.
40. 40.Turner T., Tung K.S., Tomomasa H., Wilson L.W., 1997. Acute testicular ischemia results in germ cell-specific apoptosis in the rat. Biol Reprod, 57, 1267-74.
41. 41.Türk G., Ateşşahin A., Sönmez M., Yüce A., Çeribaşi A.O., 2007. Lycopene protects against cyclosporine A-induced testicular toxicity in rats. Theriogenology, 67, 778-85.
42. 42.Velmurugan B., Santhiya S.T., Nagini S.J., 2004. Protective effect of S-allylcysteine and lycopene in combination against N-methyl-N'-nitro-N-nitrosoguanidine-induced genotoxicity. Pol J Pharmacol, 56, 241-46.
43. 43.Visioli F., Riso P., Grande S., Galli C., Porrini M.J., 2003. Protective activity of tomato products on in vivo markers of lipid oxidation. Eur J Nutr, 42, 201-06.
44. 44.Yucel C., Arslan F. D., Ekmekci S., Ulker V., Kisa E., Yucel E. E.,Uçar M., İlbey Y.O., Celik O., Basok B.i., Kozacioglu, Z., 2019. Protective effect of all-trans retinoic acid in cisplatin-induced testicular damage in rats. World J Mens Health, 37, 249-256.
45. 45.Wang Y., Zhao H., Liu Y., Li J., Nie X., Huang P., Xing, M., 2021. Environmentally relevant concentration of sulfamethoxazole-induced oxidative stress-cascaded damages in the intestine of grass carp and the therapeutic application of exogenous lycopene. Environ Pollut, 274, 116597.
46. 46.Wang Z., Fan J., Wang J., Li Y., Xiao L., Duan D., Wang Q., 2016. Protective effect of lycopene on high-fat diet-inducedcognitive impairment in rats. Neurosci Lett, 627, 185-91.