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The Effect of Zinc and Melatonin Administration on Lipid Peroxidation, IL-6 Levels, and Element Metabolism in DMBA-Induced Breast Cancer in Rats

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Abstract

The purpose of this study was to investigate the effects of zinc and melatonin administration on interleukin-6, lipid peroxidation parameters, and element metabolism in DMBA-induced breast cancer in female rats. A total of 42 recently weaned Wistar rats were divided into 5 groups as follows: control (group 1), DMBA control (group 2), DMBA + zinc (group 3), DMBA + melatonin (group 4), and DMBA + melatonin and zinc (group 5). Malondialdehyde (MDA) and glutathione (GSH) levels in breast tissue and blood samples were determined via spectrophotometric methods. In addition, iron, magnesium, zinc, and copper levels in serum samples were determined by atomic emission, and plasma interleukin-6 levels were determined by ELISA method. The highest tissue and plasma MDA and the lowest tissue and erythrocyte GSH levels found in the study were in group 2; the highest tissue and erythrocyte GSH levels and the lowest tissue and plasma MDA levels are in group 5 (P < 0.05). Iron, magnesium, and zinc levels of groups 3, 4, and 5 were higher than the DMBA group without administration (group 2), but the copper values were significantly lower (P < 0.05). The highest IL-6 levels were determined in group 2 while IL-6 levels in the DMBA group (G5) treated with combined melatonin and zinc were lower than all other breast cancer groups (P < 0.05). According to the findings obtained in this presented study, combined zinc and melatonin therapy can contribute to the prevention of tumor growth by improving the disruption in element metabolism and suppressing IL-6 levels and reducing tissue damage that causes the cancer.

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References

  1. Kubatka P, Zubor P, Busselberg D, Kwon TK, Adamek M, Petrovic D, Opatrilova R, Gazdikova K, Caprnda M, Rodrigo L, Danko J, Kruzliak P (2018) Melatonin and breast cancer: evidences from preclinical and human studies. Crit Rev Oncol Hematol 122:133–143

    PubMed  Google Scholar 

  2. Dodda BR, Bondi CD, Hasan M, Clafshenkel WP, Gallagher KM, Kotlarczyk MP, Sethi S, Buszko E, Latimer JJ, Cline JM, Witt-Enderby PA, Davis VL (2019) Co-administering melatonin with an estradiol-progesterone menopausal hormone therapy represses mammary cancer development in a mouse model of HER2-positive breast cancer. Front Oncol 9:525

    PubMed  PubMed Central  Google Scholar 

  3. Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K (2017) Melatonin, a full service anti cancer agent: inhibition of initiation, progression and metastasis. Int J Mol Sci 18(4):E843

    PubMed  Google Scholar 

  4. Bondy SC, Campbell A (2018) Mechanisms underlying tumor suppressive properties of melatonin. Int J Mol Sci 19:E2205

    PubMed  Google Scholar 

  5. Talib WH (2018) Melatonin and cancer hallmarks. Molecules 23:E518

    PubMed  Google Scholar 

  6. da Cruz RS, Andrade FO, Carioni VMO, Rosim MP, Miranda MLP, Fontelles CC, de Oliveira PV, Barbisan LF, Castro IA, Ong TP (2019) Dietary zinc deficiency or supplementation during gestation increases breast cancer susceptibility in adult female mice offspring following a J-shaped pattern and through distinct mechanisms. Food Chem Toxicol 134:110813

    PubMed  Google Scholar 

  7. Baltaci AK, Mogulkoc R, Baltaci SB (2019) Review: The role of zinc in the endocrine system. Pak J Pharm Sci 32(1):231–239

    CAS  PubMed  Google Scholar 

  8. Baltaci SB, Mogulkoc R, Baltaci AK, Emsen A, Artac H (2018) The effect of zinc and melatonin supplementation on immunity parameters in breast cancer induced by DMBA in rats. Arch Physiol Biochem 124(3):247–252

    CAS  PubMed  Google Scholar 

  9. Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M (2018) Immunotherapeutic Interleukin-6 or Interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem 25(36):4785–4806

    CAS  PubMed  Google Scholar 

  10. Kumari N, Dwarakanath BS, Das A, Bhatt AN (2016) Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol 37(9):11553–11572

    CAS  PubMed  Google Scholar 

  11. Zarogoulidis P, Yarmus L, Darwiche K, Walter R, Huang H, Li Z, Zaric B, Tsakiridis K, Zarogoulidis K (2013) Interleukin-6 cytokine: a multifunctional glycoprotein for cancer. Immunome Res 9(62):16535

    PubMed  PubMed Central  Google Scholar 

  12. Mihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86(1):271–278

    CAS  PubMed  Google Scholar 

  13. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25(1):192–205

    CAS  PubMed  Google Scholar 

  14. Hadley M, Draper HH (1990) Isolation of a guanine-malondialdehyde adduct from rat and human urine. Lipids 25(2):82–85

    CAS  PubMed  Google Scholar 

  15. Atroshi F, Sankari S, Osterberg S, Sandholm M (1981) Variation of erythrocyte glutathione peroxidase activity in Finn sheep. Res Vet Sci 31(3):267–271

    CAS  PubMed  Google Scholar 

  16. Gan H, Zhang Y, Zhou Q, Zheng L, Xie X, Veeraraghavan VP, Mohan SK (2019) Zingerone induced caspase-dependent apoptosis in MCF-7 cells and prevents 7,12-dimethylbenz(a) anthracene-induced mammary carcinogenesis in experimental rats. J Biochem Mol Toxicol 33(10):e22387

    CAS  PubMed  Google Scholar 

  17. Rajendran J, Pachaiappan P, Subramaniyan S (2019) Dose-dependent chemopreventive effects of citronellol in DMBA-induced breast cancer among rats. Drug Dev Res 80(6):867–876

    CAS  PubMed  Google Scholar 

  18. Zeweil MM, Sadek KM, Taha NM, El-Sayed Y, Menshawy S (2019) Graviola attenuates DMBA-induced breast cancer possibly through augmenting apoptosis and antioxidant pathway and downregulating estrogen receptors. Environ Sci Pollut Res Int 26(15):15209–15217

    CAS  PubMed  Google Scholar 

  19. Hecht F, Pessoa CF, Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS (2016) The role of oxidative stress on breast cancer development and therapy. Tumour Biol 37(4):4281–4291

    CAS  PubMed  Google Scholar 

  20. Gurer-Orhan H, Ince E, Konyar D, Saso L, Suzen S (2018) The role of oxidative stress modulators in breast cancer. Curr Med Chem 25(33):4084–4101

    CAS  PubMed  Google Scholar 

  21. Borges de Araújo CG, Oliveira do Nascimento Holanda A, de Souza Rocha CV, Soares do Nascimento AP, Simplício Revoredo CM, Borges da Silva B, do Nascimento Nogueira N, do Nascimento Marreiro D (2015) Relationship between zincemia, superoxide dismutase activity and marker of oxidatıve stress in women with breast cancer. Nutr Hosp 32(2):785–791

    PubMed  Google Scholar 

  22. Famurewa AC, Ekeleme-Egedigwe CA, David EE, Eleazu CO, Folawiyo AM, Obasi NA (2020) Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats. Toxicol Mech Methods 30(2):115–123

    CAS  PubMed  Google Scholar 

  23. Amin AH, El-Missiry MA, Othman AI, Ali DA, Gouida MS, Ismail AH (2019) Ameliorative effects of melatonin against solid Ehrlich carcinoma progression in female mice. J Pineal Res 67(2):e12585

    PubMed  Google Scholar 

  24. Luo M, Shang L, Brooks MD, Jiagge E, Zhu Y, Buschhaus JM, Conley S, Fath MA, Davis A, Gheordunescu E, Wang Y, Harouaka R, Lozier A, Triner D, McDermott S, Merajver SD, Luker GD, Spitz DR, Wicha MS (2018) Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab 28(1):69–86.e6

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Didžiapetrienė J, Kazbarienė B, Tikuišis R, Dulskas A, Dabkevičienė D, Lukosevičienė V, Kontrimavičiūtė E, Sužiedėlis K, Ostapenko V (2020) Oxidant/antioxidant status of breast cancer patients in pre- and post-operative periods. Medicina (Kaunas) 56(2):E70

    Google Scholar 

  26. Gumulec J, Masarik M, Krizkova S, Adam V, Hubalek J, Hrabeta J, Eckschlager T, Stiborova M, Kizek R (2011) Insight to physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma. Curr Med Chem 18(33):5041–5051

    CAS  PubMed  Google Scholar 

  27. Al-Saran N, Subash-Babu P, Al-Nouri DM, Alfawaz HA, Alshatwi AA (2016) Zinc enhances CDKN2A, pRb1 expression and regulates functional apoptosis via upregulation of p53 and p21 expression in human breast cancer MCF-7 cell. Environ Toxicol Pharmacol 47:19–27

    CAS  PubMed  Google Scholar 

  28. Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T (2017) Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology 25(1):11–24

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB (2017) Melatonin for the prevention and treatment of cancer. Oncotarget 8(24):39896–39921

    PubMed  PubMed Central  Google Scholar 

  30. Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE (2015) Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 22(3):183–204

    Google Scholar 

  31. Chang VC, Cotterchio M, Khoo E (2019) Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis. BMC Cancer 19(1):543

    PubMed  PubMed Central  Google Scholar 

  32. Elliott RL, Head JF, McCoy JL (1994) Relationship of serum and tumor levels of iron and iron-binding proteins to lymphocyte immunity against tumor antigen in breast cancer patients. Breast Cancer Res Treat 30(3):305–309

    CAS  PubMed  Google Scholar 

  33. Rajizadeh A, Mozaffari-Khosravi H, Zavar-Reza J, Shiryazdi SM (2017) Comparison of hematological parameters, iron levels, and oxidative stress in women with and without breast cancer: a case-control study. Med J Islam Repub Iran 31:114

    PubMed  PubMed Central  Google Scholar 

  34. Quintana Pacheco DA, Sookthai D, Graf ME, Schübel R, Johnson T, Katzke VA, Kaaks R, Kühn T (2018) Iron status in relation to cancer risk and mortality: findings from a population-based prospective study. Int J Cance 143(3):561–569

    CAS  Google Scholar 

  35. Hennigar SR, Kelley AM, McClung JP (2016) Metallothionein and zinc transporter expression in circulating human blood cells as biomarkers of zinc status: a systematic review. Adv Nutr 7(4):735–746

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jouybari L, Kiani F, Akbari A, Sanagoo A, Sayehmiri F, Aaseth J, Chartrand MS, Sayehmiri K, Chirumbolo S, Bjørklund G (2019) A meta-analysis of zinc levels in breast cancer. J Trace Elem Med Biol 56:90–99

    CAS  PubMed  Google Scholar 

  37. Abdelgawad IA, El-Mously RH, Saber MM, Mansour OA, Shouman SA (2015) Significance of serum levels of vitamin D and some related minerals in breast cancer patients. Int J Clin Exp Pathol 8(4):4074–4082

    PubMed  PubMed Central  Google Scholar 

  38. Choi R, Kim MJ, Sohn I, Kim S, Kim I, Ryu JM, Choi HJ, Kim JM, Lee SK, Yu J, Kim SW, Nam SJ, Lee JE, Lee SY (2018) Serum trace elements and their associations with breast cancer subgroups in Korean breast cancer patients. Nutrients 11(1):E37

    PubMed  Google Scholar 

  39. Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M, Jadidi-Niaragh F (2018) The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother 108:1415–1424

    CAS  PubMed  Google Scholar 

  40. Weng YS, Tseng HY, Chen YA, Shen PC, Al Haq AT, Chen LM, Tung YC, Hsu HL (2019) MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer. Mol Cancer 18(1):42

    PubMed  PubMed Central  Google Scholar 

  41. González-González A, García Nieto E, González A, Sánchez-Fernández C, Alonso-González C, Menéndez-Menéndez J, Gómez-Arozamena J, Cos S, Martínez-Campa C (2019) Melatonin modulation of radiation and chemotherapeutics-induced changes on differentiation of breast fibroblasts. Int J Mol Sci 20(16):E3935

    PubMed  Google Scholar 

  42. Unver N, McAllister F (2018) IL-6 family cytokines: key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev 41:10–17

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the Scientific Research Projects Coordinatorship of Selcuk University (SUBAPK; project no. 16202035).

Data

Combined zinc and melatonin treatment may contribute to prevent tumor growth by improving impairment in element metabolism and suppressing IL-6 levels and increased tissue damage that causes acceleration of cancer development.

Funding

This study was supported by the Scientific Research Projects Coordinatorship of Selcuk University (SUBAPK; project no. 16202035).

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Correspondence to Abdulkerim Kasim Baltaci.

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The authors declare that they have no confict of interest.

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This study was performed on Wistar type adult male rats.

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Research meets ethical guidelines is a required field. The study protocol was approved by Selçuk University Experimental Medicine Research and Application Center Laboratory Animals Ethics Board (No: 2016-32).

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Gulbahce-Mutlu, E., Baltaci, S.B., Menevse, E. et al. The Effect of Zinc and Melatonin Administration on Lipid Peroxidation, IL-6 Levels, and Element Metabolism in DMBA-Induced Breast Cancer in Rats. Biol Trace Elem Res 199, 1044–1051 (2021). https://doi.org/10.1007/s12011-020-02238-0

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