The protective effects of Selenium and Boron against Cyclophosphamide-induced bone marrow and blood toxicity: An in vivo study

Abstract

Thanks to their antioxidant, anti-apoptotic, anti-lipid peroxidative, and immune-boosting properties, Boron (B) and Selenium (Se) are essential trace elements for the human body. This study aims to compare the myeloid protective potentials of Se and B in Cyclophosphamide (CP)-induced bone-marrow and haematological toxicity in experimental rats considering that the myelotoxic property of this anti-cancer drug limits its use. We hypothesized that selenium has a better protective effect than boron in preventing the toxic effects of CP on bone marrow and blood cells. 1.5 mg/kg of Se and 20 mg/kg of B, which are the most frequently used optimal doses of these trace elements, were given to the animals intraperitoneally throughout the experiment. 200 mg/kg of CP was administered only on the 4th day. The animals were sacrificed to take the blood and bone marrow samples to be stored for hematological evaluations. The CP administration significantly decreased leukocyte (WBC), thrombocyte (PLT), erythrocytes (RBC), and bone marrow nucleated cell counts. On the other hand, they increased in significant amounts in the groups given Se and B along with CP when compared to those given only CP. However, Se proved to be more protective than B in preventing CP-induced bone marrow and hematologic toxicity despite not achieving statistical significance. It was, therefore, concluded that the doses used in this experiment were successful in protecting against CP-induced damage to the bone marrow and CP-related hematological toxicity.

Keywords

• Cyclophosphamide
• Selenium
• Boron
• Bone marrow
• Hematologic toxicity

Selenyum ve Bor'un Siklofosfamid kaynaklı kemik iliği ve kan toksisitesine karşı koruyucu etkileri: Bir in vivo çalışma

Abstract

Bor (B) ve Selenyum (Se), antioksidan, anti-apoptotik, anti-lipid peroksidatif ve bağışıklık güçlendirici özellikleri sayesinde insan vücudu için gerekli eser elementlerdir. Bu çalışma, Se ve B'nin Siklofosfamid (SFD) ile indüklenen kemik iliğinde miyeloid koruyucu potansiyellerini ve bu anti-kanser ilacın miyelotoksik özelliğinin kullanımını sınırladığını göz önünde bulundurarak deneysel sıçanlarda hematolojik toksisiteyi karşılaştırmayı amaçlamaktadır. SFD'nin kemik iliği ve kan hücreleri üzerindeki toksik etkilerini önlemede selenyumun bordan daha iyi bir koruyucu etkiye sahip olduğunu varsaydık. Bu eser elementlerin en sık kullanılan optimal dozları olan 1.5 mg/kg Se ve 20 mg/kg B hayvanlara deney boyunca intraperitoneal olarak verildi. Sadece 4. günde 200 mg/kg SFD uygulandı. Hayvanlar sakrifiye edilerek hematolojik değerlendirmeler için kan ve kemik iliği örnekleri alındı. SFD uygulaması, lökosit (WBC), trombosit (PLT), eritrositler (RBC) ve kemik iliği çekirdekli hücre sayılarını önemli ölçüde azalttı. Öte yandan, SFD ile birlikte Se ve B verilen gruplarda, sadece SFD verilenlere göre önemli miktarlarda arttı. Ancak Se'nin, istatistiksel anlamlılık elde edememesine rağmen, SFD'nin neden olduğu kemik iliği ve hematolojik toksisiteyi önlemede B'den daha koruyucu olduğu kanıtlanmıştır. Bu nedenle, bu deneyde kullanılan dozların, kemik iliğinde SFD'nin neden olduğu hasara ve SFD'e bağlı hematolojik toksisiteye karşı korumada başarılı olduğu sonucuna varıldı.

Keywords

• Siklofosfamid
• Selenyum
• Bor
• Kemik iliği
• Hematolojik Toksisite

References

1. [1] Thun, M. J., DeLancey, J. O., Center, M. M., Jemal, A., and Ward, E. M. (2010). The global burden of cancer: priorities for prevention, Carcinogenesis 31 100-110.
2. [2] Iqubal, A., Iqubal, M. K., Sharma, S., Ansari, M. A., Najmi, A. K., Ali, S. M., Ali, J., and Haque, S. E. (2019). Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision, Life Sciences 218, 112-131.
3. [3] Ashry, N. A., Gameil, N. M., and Suddek, G. M. (2013). Modulation of cyclophosphamide-induced early lung injury by allicin, Pharmaceutical Biology, 51 806-811.
4. [4] Kalaycioglu, M. E., Lichtin, A. E., Andresen, S. W., Tuason, L., and Bolwell, B. (1995). High-dose busulfan and cyclophosphamide followed by autologous bone marrow transplantation and/or peripheral blood progenitor cell rescue for metastatic breast cancer. American Journal of Clinical Oncology 18, 491-494.
5. [5] Kumar, K., and Kuttan, R. J. P. (2005). Chemoprotective activity of an extract of Phyllanthus amarus against cyclophosphamide induced toxicity in mice. Phytomedicine 12, 494-500.
6. [6] Senthilkumar, S., Devaki, T., Manohar, B. M., and Babu, M. S. (2006). Effect of squalene on cyclophosphamide-induced toxicity. Clinica Chimica Acta 364, 335-342.
7. [7] Ozabacigil, F., Beydemir, S., Ciftci, M., Gumustekin, K., and Bakan, N. (2008). Cisplatin and 5-fluorouracil inhibits 6-phosphogluconate dehydrogenase activity in human erythrocytes in vitro and in vivo. Asian Journal of Chemistry 20, 3189.
8. [8] Cengiz, M. (2018). Hematoprotective effect of boron on cyclophosphamide toxicity in rats. Cellular and Molecular Biology 64, 62-65.

9. [9] Ağgül, A. G., Gür, F., and Gülaboğlu, M. (2021). Streptozotocin‐Induced Oxidative Stress in Rats: The Protective Role of Olive Leaf Extract. Bulletin of the Korean Chemical Society,42, 180-187.
10. [10] Fatma, G., Ağgül, A. G., and Gülaboğlu, M. (2020). Su ile hazırlanan zeytin yaprağı özütünün ratlarda streptozotosin kaynaklı oksidatif stres ve lipit peroksidasyonu üzerine etkileri. Journal of the Institute of Science and Technology 10, 2406-2415.
11. [11] Ayhanci, A., Günes, S., Sahinturk, V., Appak, S., Uyar, R., Cengiz, M., Altuner, Y., and Yaman, S. (2010). Seleno L-methionine acts on cyclophosphamide-induced kidney toxicity. Biological Trace Element Research 136, 171-179.
12. [12] Sengul, E., Gelen, V., Yildirim, S., Tekin, S., and Dag, Y. (2021). The Effects of Selenium in Acrylamide-Induced Nephrotoxicity in Rats: Roles of Oxidative Stress, Inflammation, Apoptosis, and DNA Damage. Biological Trace Element Research 199 (1), 173-184.
13. [13] Rayman, M. P. (2000). The importance of selenium to human health. Lancet 356, 233-241.
14. [14] Ip, C. T. (1998). Lessons from basic research in selenium and cancer prevention. The Journal of Nutrition 128 1845-1854.
15. [15] Lin, X., Wang, L., Zhao, J., He, L., Cui, L., Gao, Y., Chen, C., Fan, Y., Li, B., and Li, Y. F. (2021). Nanosafety evaluation through feces: a comparison between selenium nanoparticles and selenite in rats. NanoToday 36, 101010.
16. [16] Jin, Y., He, Y., Liu, L., Tao, W., Wang, G., Sun, W., Pei, X., Xiao, Z., Wang, H., and Wang, M. (2021). Effects of Supranutritional Selenium Nanoparticles on Immune and Antioxidant Capacity in Sprague-Dawley Rats. Biological Trace Elements Research 1-9.
17. [17] Sogut, I., Paltun, S. O., Tuncdemir, M., Ersoz, M., Hurdag, C. (2018). The antioxidant and antiapoptotic effect of boric acid on hepatoxicity in chronic alcohol-fed rats. Canadian Journal of Physiology and Pharmacology 96, 404-411.
18. [18] Cengiz, M. (2018). Ratlarda siklofosfamid nedenli kardiyotoksisite üzerine borik asitin koruyucu etkileri. Bitlis Eren Üniversitesi Fen Bilimleri Dergisi 7, 113-118.
19. [19] Farfán-García, E., Castillo-Mendieta, N., Ciprés-Flores, F., Padilla-Martínez, I., Trujillo-Ferrara, J., and Soriano-Ursúa, M. A. (2016). Current data regarding the structure-toxicity relationship of boron-containing compounds. Toxicology Letters 258, 115-125.
20. [20] Cengiz, M., Sahinturk, V., Yildiz, S. C., Şahin, İ. K., Bilici, N., Yaman, S. O., Altuner, Y., Appak-Baskoy, S., and Ayhanci, A. (2020). Cyclophosphamide induced oxidative stress, lipid per oxidation, apoptosis and histopathological changes in rats. Protective role of boron, Journal of Trace Elements in Medicine Biology 62, 126574.
21. [21] Yılmaz, S., Ustundag, A., Ulker, O. C., and Duydu, Y. (2016). Protective effect of boric acid on oxidative DNA damage in Chinese hamster lung fibroblast V79 cell line. Cell Journal 17, 748.
22. [22] Cengiz, M. (2018). Boric acid protects against cyclophosphamide-induced oxidative stress and renal damage in rats. Cellular and Molecular Biology 64, 11-14.
23. [23] Ayhanci, A., Tanriverdi, D. T., Sahinturk, V., Cengiz, M., Appak-Baskoy, S., and Sahin Kulcanay, I. (2020). Protective effects of boron on cyclophosphamide-induced bladder damage and oxidative stress in rats. Biological Trace Element Research 197, 184-191.
24. [24] Ince, S., Kucukkurt, I., Demirel, H. H., Acaroz, D. A., Akbel, E., and Cigerci, I. H. (2014). Protective effects of boron on cyclophosphamide induced lipid peroxidation and genotoxicity in rats. Chemosphere 108, 197-204.
25. [25] Güney, T. G., Çalişkan, A., Fatih, K., Gündoğdu, A. Ç., and Özbayer, C. (2022). Sıçan böbrek dokusunda etanolün akut toksisitesi ve borik asitin koruyucu rolü. Biyolojik Çeşitlilik ve Koruma 15, 107-113.
26. [26] Gundogdu, G., Nalci, K. A., Ugur Kaplan, A. B., Gundogdu, K., Demirci, T., Demirkaya Miloglu, F., Hacımuftuoglu, A., and Cetin, M. (2020). The Evaluation of the Effects of Nanoemulsion Formulations Containing Boron and/or Zinc on the Wound Healing in Diabetic Rats. The International Journal of Lower Extremity Wounds 1534734620961892.
27. [27] Altromin. (2021). Breeding diet for rats and mice. Altromin.
28. [28] Lerza, R., Bogliolo, G., Mencoboni, M., Saviane, A., and Pannacciulli, I. (1988). Studies on hemotoxicity of cyclophosphamide, doxorubicin and cis-diamminodichloroplatinum combined with sodium-2-mercaptoethane sulfonate. Tumori Journal 74, 333-337.
29. [29] Cengiz, M., Yeşildağ, Ö., and Ayhancı, A. (2018). Siklofosfamid Nedenli Hematoksisite Üzerine Karvakrolün Sitoprotektif Etkileri. Türkiye Tarımsal Araştırmalar Dergisi 5, 125-130.
30. [30] Patra, K., Bose, S., Sarkar, S., Rakshit, J., Jana, S., Mukherjee, A., Roy, A., Mandal, D. P., and Bhattacharjee, S. (2012). Amelioration of cyclophosphamide induced myelosuppression and oxidative stress by cinnamic acid. Chemico-Biological Interactions 195, 231-239.
31. [31] Iqubal, A., Haque, S. E., Sharma, S., Ansari, M. A., Khan, V., and Iqubal, M. K. (2018). Clinical updates on drug-induced cardiotoxicity. International Journal of Pharmaceutical Sciences Research 9, 16-26.
32. [32] Ayhanci, A., Heybeli, N., Kulcanay Sahin, İ. and Cengiz, M. (2019). Myelosuppression and Oxidative Stress Induced by Cyclophosphamide in Rats: The Protective Role of Selenium. Adıyaman University Journal of Science, 9 (2), 252-265.
33. [33] Iqubal, A., Syed, M. A., Haque, M. M., Najmi, A. K., Ali, J., and Haque, S. E. (2020). Effect of nerolidol on cyclophosphamide-induced bone marrow and hematologic toxicity in Swiss albino mice. Experimental Hematology 82, 24-32.
34. [34] Owumi, S. E., and Dim, U. J. (2019). Biochemical alterations in diclofenac-treated rats: Effect of selenium on oxidative stress, inflammation, and hematological changes. Toxicology Research Application 3, 2397847319874359.
35. [35] Hunt, C. D. (2005). Boron. In: P.M. Coates, M.R. Blackman, G. Cragg, M. Levine, J. Moss, J. White, Editors. Encyclopedia of Dietary Supplements. New York: Marcel Dekker/Taylor and Francis Group p. 55-63.