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An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages

Year 2022, Volume: 14 Issue: 1, 104 - 113, 14.03.2022
https://doi.org/10.18521/ktd.1049919

Abstract

Objective: Doxorubicin (DOX), one of the chemotherapeutic drugs utilized in cancer treatment, has limited clinical use due to its serious toxic effects on non-target organs. The purpose of this study is to reveal the harmful effects of DOX in rat liver and the possible protective effect of propolis (PRPLS), a mixture of various herbal products collected by honeybees, on these damages by Attenuated Total Reflection-Fourier Transformation Infrared (ATR-FTIR) spectroscopy.
Methods: Sprague dawley rats were separated into 4 groups; control, DOX (cumulative dose: 15 mg/kg), PRPLS (200 mg/kg) and DOX + PRPLS. The rats were given 200 mg/kg PRPLS by oral gavage daily for 20 consecutive days and 2.5 mg/kg DOX intraperitoneally on days 10, 12, 14, 16, 18 and 20 of the experiment. 24 hrs after the last administrations, liver samples were collected and examined by ATR-FTIR spectroscopy.
Results: DOX caused a decrease in the amount of glycogen and nucleic acids, an increase in the amount of lipids and proteins and some important changes in the metabolism, structure and conformation of these molecules in the liver. DOX also induced lipid peroxidation, an increase in membrane fluidity, a decrease in membrane order and protein denaturation. PRPLS did not induce any toxic effect on the liver when it was given alone and PRPLS administered before DOX was not effective to eliminate these harmful effects of DOX.
Conclusions: DOX caused significant structural and compositional changes in liver tissue and PRPLS was inadequate to prevent these changes at the dose and time used here.

Supporting Institution

Duzce University

Project Number

BAP (2019.05.01.936)

References

  • 1. Renu K, Sruthy KB, Parthiban S, Sugunapriyadharshini S, George A, Tirupathi Pichiah PB, et al. Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance. European Journal of Pharmacology. 2019;843:162-76. doi: 10.1016/j.ejphar.2018.11.018.
  • 2. Rizk SM, Zaki HF, Mina MA. Propolis attenuates doxorubicin-induced testicular toxicity in rats. Food and Chemical Toxicology. 2014;67:176-86. doi: 10.1016/j.fct.2014.02.031.
  • 3. Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Archives of Medical Research. 2007;38(4):380-5. doi: 10.1016/j.arcmed.2007.01.007.
  • 4. Singla S, Kumar NR, Kaur J. In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats. Toxicology International. 2014;21(2):191-5. doi: 10.4103/0971-6580.139808.
  • 5. Alyane M, Kebsa LB, Boussenane H, Rouibah H, Lahouel M. Cardioprotective effects and mechanism of action of polyphenols extracted from propolis against doxorubicin toxicity. Pakistan Journal of Pharmaceutical Sciences. 2008;21(3):201-9.
  • 6. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. Journal of Hepatology. 2012;56(4):952-64. doi: 10.1016/j.jhep.2011.08.025.
  • 7. Kocot J, Kiełczykowska M, Luchowska-Kocot D, Kurzepa J, Musik I. Antioxidant Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical Application. Oxidative Medicine and Cellular Longevity. 2018;2018:7074209. doi: 10.1155/2018/7074209.
  • 8. Bueno-Silva B, Marsola A, Ikegaki M, Alencar SM, Rosalen PL. The effect of seasons on Brazilian red propolis and its botanical source: chemical composition and antibacterial activity. Natural Product Research. 2017;31(11):1318-24. doi: 10.1080/14786419.2016.1239088.
  • 9. Sforcin JM. Biological Properties and Therapeutic Applications of Propolis. Phytotherapy Research : PTR. 2016;30(6):894-905. doi: 10.1002/ptr.5605.
  • 10. Wided K, Hassiba R, Mesbah L. Polyphenolic fraction of Algerian propolis reverses doxorubicin induced oxidative stress in liver cells and mitochondria. Pakistan Journal of Pharmaceutical Sciences. 2014;27(6):1891-7.
  • 11. Cakmak-Arslan G, Haksoy H, Goc-Rasgele P, Kekecoglu M. Determination of the dose-dependent toxic effects of mad honey on mouse liver using ATR-FTIR spectroscopy. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2020;228:117719. doi:10.1016/j.saa.2019.117719
  • 12. Ozek NS, Tuna S, Erson-Bensan AE, Severcan F. Characterization of microRNA-125b expression in MCF7 breast cancer cells by ATR-FTIR spectroscopy. The Analyst. 2010;135(12):3094-102. doi:10.1039/C0AN00543F
  • 13. Gurbanov R, Bilgin M, Severcan F. Restoring effect of selenium on the molecular content, structure and fluidity of diabetic rat kidney brush border cell membrane. Biochimica et Biophysica Acta. 2016;1858(4):845-54. doi: 10.1016/j.bbamem.2016.02.001
  • 14. Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratislavske Lekarske Listy. 2017;118(5):273-7. doi: 10.4149/BLL_2017_054
  • 15. Khalilzadeh M, Abdollahi A, Abdolahi F, Abdolghaffari AH, Dehpour AR, Jazaeri F. Protective effects of magnesium sulfate against doxorubicin induced cardiotoxicity in rats. Life Sciences. 2018;207:436-41. doi: 10.1016/j.lfs.2018.06.022
  • 16. Keser H, Bozkurt Girit Ö, Majeed M, Nayak M, Bilgin MD. Pterostilbene administration improves the recovery potential of extremely low-frequency magnetic field in acute renal ischemia-reperfusion injury: an FTIR spectroscopic study. Turkish Journal of Biology 2020;44(1):48-60. doi: 10.3906/biy-1907-18
  • 17. Babenko NA, Kharchenko VS. Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D. International Journal of Endocrinology. 2015;2015:794838. doi:10.1155/2015/794838
  • 18. Bilgic S, Ozgocmen M. The protective effect of misoprostol against doxorubicin induced liver injury. Biotechnic & Histochemistry 2019;94(8):583-91. doi: 10.1080/10520295.2019.1605457
  • 19. Gu J, Zhang Y, Xu D, Zhao Z, Zhang Y, Pan Y, et al. Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver[S]. Journal of Lipid Research. 2015;56(7):1329-39. doi: 10.1194/jlr.M056978
  • 20. Peng C, Chiappini F, Kbb áková S, Danulot M, Sandt C, Samuel D, et al. Vibrational signatures to discriminate liver steatosis grades. The Analyst. 2015;140 4:1107-18. doi: 10.1039/C4AN01679C
  • 21. Oz E, Erbaş D, Sürücü HS, Düzgün E. Prevention of doxorubicin-induced cardiotoxicity by melatonin. Molecular and Cellular Biochemistry. 2006;282(1-2):31-7. doi: 10.1007/s11010-006-1153-9
  • 22. de Zwart LL, Meerman JH, Commandeur JN, Vermeulen NP. Biomarkers of free radical damage applications in experimental animals and in humans. Free Radical Biology & Medicine. 1999;26(1-2):202-26. doi: 10.1016/s0891-5849(98)00196-8
  • 23. Afsar T, Razak S, Almajwal A. Effect of Acacia hydaspica R. Parker extract on lipid peroxidation, antioxidant status, liver function test and histopathology in doxorubicin treated rats. Lipids in Health and Disease. 2019;18(1):126. doi: 10.1186/s12944-019-1051-2
  • 24. Ozdoğan K, Taşkın E, Dursun N. Protective effect of carnosine on adriamycin-induced oxidative heart damage in rats. The Anatolian Journal of Cardiology. 2011;11(1):3-10. doi: 10.5152/akd.2011.003
  • 25. Kwiecień I, Michalska M, Włodek L. The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice. European Journal of Pharmacology. 2006;550(1-3):39-46. doi: 10.1016/j.ejphar.2006.09.001
  • 26. Olivares-Corichi IM, Ceballos G, Medina-Santillan R, Medina-Navarro R, Guzman-Grenfell AM, Hicks JJ. Oxidation by reactive oxygen species (ROS) alters the structure of human insulin and decreases the insulin-dependent D-glucose-C14 utilization by human adipose tissue. Frontiers in Bioscience : A Journal and Virtual Library. 2005;10:3127-31. doi: 10.2741/1769
  • 27. Wang B, Ma Y, Kong X, Ding X, Gu H, Chu T, et al. NAD(+) administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage. Chemico-biological Interactions. 2014;212:65-71. doi: 10.1016/j.cbi.2014.01.013
  • 28. Prasanna PL, Renu K, Valsala Gopalakrishnan A. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sciences. 2020;250:117599. doi: 10.1016/j.lfs.2020.117599
  • 29. Megli FM, Sabatini K. Mitochondrial phospholipid bilayer structure is ruined after liver oxidative injury in vivo. FEBS Letters. 2004;573(1-3):68-72. doi: 10.1016/j.febslet.2004.07.057

Doksorubisinin Karaciğer Dokusunda Oluşturduğu Hasarın ve Propolisin Bu Hasar Üzerindeki Potansiyel Koruyucu Etkisinin Değerlendirilmesi

Year 2022, Volume: 14 Issue: 1, 104 - 113, 14.03.2022
https://doi.org/10.18521/ktd.1049919

Abstract

Amaç: Kanser tedavisinde kullanılan kemoterapötik ilaçlardan birisi olan doksorubisin (DOX), hedef dışı organlar üzerindeki ciddi toksik etkileri nedeniyle sınırlı klinik kullanıma sahiptir. Bu çalışmanın amacı, DOX'un sıçan karaciğerindeki zararlı etkilerini ve bal arıları tarafından toplanan çeşitli bitkisel ürünlerin bir karışımı olan propolis (PRPLS)'in bu zararlar üzerindeki olası koruyucu etkisini Azaltılmış Toplam Yansıma-Fourier Dönüşüm Kızılötesi (ATR-FTIR) spektroskopisi ile ortaya çıkarmaktır.
Gereç ve Yöntem: Sprague dawley sıçanlar 4 gruba ayrılmıştır; kontrol, DOX (kümülatif doz: 15 mg/kg), PRPLS (200 mg/kg) ve DOX + PRPLS. Sıçanlara ardışık 20 gün boyunca oral gavaj yoluyla günlük 200 mg/kg PRPLS ve 10, 12, 14, 16, 18 ve 20. günlerde intraperitoneal olarak 2,5 mg/kg DOX verilmiştir. Son uygulamalardan 24 saat sonra karaciğer örnekleri alınmış ve ATR-FTIR spektroskopisi ile incelenmiştir.
Bulgular: DOX karaciğerde glikojen ve nükleik asit miktarında azalmaya, lipid ve protein miktarında artışa ve bu moleküllerin metabolizması, yapısı ve konformasyonlarında bazı önemli değişikliklere sebep olmuştur. DOX, ayrıca lipid peroksidasyonuna, membran akışkanlığında bir artışa, membran düzeninde bir azalmaya ve protein denatürasyonuna neden olmuştur. PRPLS tek başına verildiğinde karaciğer üzerinde herhangi bir toksik etki oluşturmamış ve DOX'tan önce verilen PRPLS, DOX'un zararlı etkilerini ortadan kaldırmada etkili olamamıştır.
Sonuç: DOX, karaciğer dokusunda önemli yapısal ve kompozisyonel değişikliklere neden olmuş ve PRPLS bu çalışmada kullanılan doz ve zamanda bu değişiklikleri önlemekte yetersiz kalmıştır.

Project Number

BAP (2019.05.01.936)

References

  • 1. Renu K, Sruthy KB, Parthiban S, Sugunapriyadharshini S, George A, Tirupathi Pichiah PB, et al. Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance. European Journal of Pharmacology. 2019;843:162-76. doi: 10.1016/j.ejphar.2018.11.018.
  • 2. Rizk SM, Zaki HF, Mina MA. Propolis attenuates doxorubicin-induced testicular toxicity in rats. Food and Chemical Toxicology. 2014;67:176-86. doi: 10.1016/j.fct.2014.02.031.
  • 3. Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Archives of Medical Research. 2007;38(4):380-5. doi: 10.1016/j.arcmed.2007.01.007.
  • 4. Singla S, Kumar NR, Kaur J. In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats. Toxicology International. 2014;21(2):191-5. doi: 10.4103/0971-6580.139808.
  • 5. Alyane M, Kebsa LB, Boussenane H, Rouibah H, Lahouel M. Cardioprotective effects and mechanism of action of polyphenols extracted from propolis against doxorubicin toxicity. Pakistan Journal of Pharmaceutical Sciences. 2008;21(3):201-9.
  • 6. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. Journal of Hepatology. 2012;56(4):952-64. doi: 10.1016/j.jhep.2011.08.025.
  • 7. Kocot J, Kiełczykowska M, Luchowska-Kocot D, Kurzepa J, Musik I. Antioxidant Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical Application. Oxidative Medicine and Cellular Longevity. 2018;2018:7074209. doi: 10.1155/2018/7074209.
  • 8. Bueno-Silva B, Marsola A, Ikegaki M, Alencar SM, Rosalen PL. The effect of seasons on Brazilian red propolis and its botanical source: chemical composition and antibacterial activity. Natural Product Research. 2017;31(11):1318-24. doi: 10.1080/14786419.2016.1239088.
  • 9. Sforcin JM. Biological Properties and Therapeutic Applications of Propolis. Phytotherapy Research : PTR. 2016;30(6):894-905. doi: 10.1002/ptr.5605.
  • 10. Wided K, Hassiba R, Mesbah L. Polyphenolic fraction of Algerian propolis reverses doxorubicin induced oxidative stress in liver cells and mitochondria. Pakistan Journal of Pharmaceutical Sciences. 2014;27(6):1891-7.
  • 11. Cakmak-Arslan G, Haksoy H, Goc-Rasgele P, Kekecoglu M. Determination of the dose-dependent toxic effects of mad honey on mouse liver using ATR-FTIR spectroscopy. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2020;228:117719. doi:10.1016/j.saa.2019.117719
  • 12. Ozek NS, Tuna S, Erson-Bensan AE, Severcan F. Characterization of microRNA-125b expression in MCF7 breast cancer cells by ATR-FTIR spectroscopy. The Analyst. 2010;135(12):3094-102. doi:10.1039/C0AN00543F
  • 13. Gurbanov R, Bilgin M, Severcan F. Restoring effect of selenium on the molecular content, structure and fluidity of diabetic rat kidney brush border cell membrane. Biochimica et Biophysica Acta. 2016;1858(4):845-54. doi: 10.1016/j.bbamem.2016.02.001
  • 14. Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratislavske Lekarske Listy. 2017;118(5):273-7. doi: 10.4149/BLL_2017_054
  • 15. Khalilzadeh M, Abdollahi A, Abdolahi F, Abdolghaffari AH, Dehpour AR, Jazaeri F. Protective effects of magnesium sulfate against doxorubicin induced cardiotoxicity in rats. Life Sciences. 2018;207:436-41. doi: 10.1016/j.lfs.2018.06.022
  • 16. Keser H, Bozkurt Girit Ö, Majeed M, Nayak M, Bilgin MD. Pterostilbene administration improves the recovery potential of extremely low-frequency magnetic field in acute renal ischemia-reperfusion injury: an FTIR spectroscopic study. Turkish Journal of Biology 2020;44(1):48-60. doi: 10.3906/biy-1907-18
  • 17. Babenko NA, Kharchenko VS. Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D. International Journal of Endocrinology. 2015;2015:794838. doi:10.1155/2015/794838
  • 18. Bilgic S, Ozgocmen M. The protective effect of misoprostol against doxorubicin induced liver injury. Biotechnic & Histochemistry 2019;94(8):583-91. doi: 10.1080/10520295.2019.1605457
  • 19. Gu J, Zhang Y, Xu D, Zhao Z, Zhang Y, Pan Y, et al. Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver[S]. Journal of Lipid Research. 2015;56(7):1329-39. doi: 10.1194/jlr.M056978
  • 20. Peng C, Chiappini F, Kbb áková S, Danulot M, Sandt C, Samuel D, et al. Vibrational signatures to discriminate liver steatosis grades. The Analyst. 2015;140 4:1107-18. doi: 10.1039/C4AN01679C
  • 21. Oz E, Erbaş D, Sürücü HS, Düzgün E. Prevention of doxorubicin-induced cardiotoxicity by melatonin. Molecular and Cellular Biochemistry. 2006;282(1-2):31-7. doi: 10.1007/s11010-006-1153-9
  • 22. de Zwart LL, Meerman JH, Commandeur JN, Vermeulen NP. Biomarkers of free radical damage applications in experimental animals and in humans. Free Radical Biology & Medicine. 1999;26(1-2):202-26. doi: 10.1016/s0891-5849(98)00196-8
  • 23. Afsar T, Razak S, Almajwal A. Effect of Acacia hydaspica R. Parker extract on lipid peroxidation, antioxidant status, liver function test and histopathology in doxorubicin treated rats. Lipids in Health and Disease. 2019;18(1):126. doi: 10.1186/s12944-019-1051-2
  • 24. Ozdoğan K, Taşkın E, Dursun N. Protective effect of carnosine on adriamycin-induced oxidative heart damage in rats. The Anatolian Journal of Cardiology. 2011;11(1):3-10. doi: 10.5152/akd.2011.003
  • 25. Kwiecień I, Michalska M, Włodek L. The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice. European Journal of Pharmacology. 2006;550(1-3):39-46. doi: 10.1016/j.ejphar.2006.09.001
  • 26. Olivares-Corichi IM, Ceballos G, Medina-Santillan R, Medina-Navarro R, Guzman-Grenfell AM, Hicks JJ. Oxidation by reactive oxygen species (ROS) alters the structure of human insulin and decreases the insulin-dependent D-glucose-C14 utilization by human adipose tissue. Frontiers in Bioscience : A Journal and Virtual Library. 2005;10:3127-31. doi: 10.2741/1769
  • 27. Wang B, Ma Y, Kong X, Ding X, Gu H, Chu T, et al. NAD(+) administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage. Chemico-biological Interactions. 2014;212:65-71. doi: 10.1016/j.cbi.2014.01.013
  • 28. Prasanna PL, Renu K, Valsala Gopalakrishnan A. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sciences. 2020;250:117599. doi: 10.1016/j.lfs.2020.117599
  • 29. Megli FM, Sabatini K. Mitochondrial phospholipid bilayer structure is ruined after liver oxidative injury in vivo. FEBS Letters. 2004;573(1-3):68-72. doi: 10.1016/j.febslet.2004.07.057
There are 29 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Articles
Authors

Nursen Orak This is me 0000-0003-3789-3589

Gülgün Çakmak Arslan 0000-0003-4326-1780

Salih Tunç Kaya 0000-0002-4133-407X

Project Number BAP (2019.05.01.936)
Publication Date March 14, 2022
Acceptance Date February 20, 2022
Published in Issue Year 2022 Volume: 14 Issue: 1

Cite

APA Orak, N., Çakmak Arslan, G., & Kaya, S. T. (2022). An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages. Konuralp Medical Journal, 14(1), 104-113. https://doi.org/10.18521/ktd.1049919
AMA Orak N, Çakmak Arslan G, Kaya ST. An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages. Konuralp Medical Journal. March 2022;14(1):104-113. doi:10.18521/ktd.1049919
Chicago Orak, Nursen, Gülgün Çakmak Arslan, and Salih Tunç Kaya. “An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages”. Konuralp Medical Journal 14, no. 1 (March 2022): 104-13. https://doi.org/10.18521/ktd.1049919.
EndNote Orak N, Çakmak Arslan G, Kaya ST (March 1, 2022) An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages. Konuralp Medical Journal 14 1 104–113.
IEEE N. Orak, G. Çakmak Arslan, and S. T. Kaya, “An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages”, Konuralp Medical Journal, vol. 14, no. 1, pp. 104–113, 2022, doi: 10.18521/ktd.1049919.
ISNAD Orak, Nursen et al. “An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages”. Konuralp Medical Journal 14/1 (March 2022), 104-113. https://doi.org/10.18521/ktd.1049919.
JAMA Orak N, Çakmak Arslan G, Kaya ST. An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages. Konuralp Medical Journal. 2022;14:104–113.
MLA Orak, Nursen et al. “An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages”. Konuralp Medical Journal, vol. 14, no. 1, 2022, pp. 104-13, doi:10.18521/ktd.1049919.
Vancouver Orak N, Çakmak Arslan G, Kaya ST. An Evaluation of Damages Caused by Doxorubicin in Liver Tissue and Potential Protective Effect of Propolis on These Damages. Konuralp Medical Journal. 2022;14(1):104-13.