Research Article
BibTex RIS Cite

The role of oxidative stress, apoptosis and altered TRPM2 channel activation in doxorubicin-induced liver injury; the protective effect of selenium

Year 2024, Volume: 8 Issue: 2, 118 - 124, 30.08.2024
https://doi.org/10.30565/medalanya.1483307

Abstract

Aim: Doxorubicin (DOXR) is frequently used alone or as combination therapy in the treatment of various types of cancer. Although dose-dependent side effects are known, its effects on liver health are not fully known. This study aimed to investigate the role of the transient receptor potential melastatin-2 (TRPM2) channel in DOXR-treated rats using the TRPM-2 channel blocker N-(p-amylcinamoyl) anthranilic acid (ACA) and to investigate the protective effects of selenium (Se).

Methods: Rats were allocated into six groups, each containing ten rats: control, DMSO, DOXR, DOXR + Se, DOXR + ACA, and DOXR + ACA + Se. Serum levels of AST, ALT, LDH, triglycerides, and total cholesterol were measured. Additionally, liver tissues were subjected to immunohistochemical tests for TRPM2 channel, 8-OHdG, and caspase-3 (Casp-3) expressions and also histopathological evaluation.

Results: Serum AST, ALT, LDH, triglyceride and total cholesterol levels, as well as liver 8-OHdG, TRPM2 channel and Casp-3 expressions in the DOXR group were significantly higher than in the DOXR + Se, DOXR + ACA and DOXR + ACA + Se groups (p < 0.05). However, these parameters were significantly reduced in the Se and ACA-treated groups compared to the DOXR group (p < 0.05).

Conclusions: The results suggest that simultaneous administration of Se or ACA with DOXR may provide an effective therapeutic approach to combat DOXR-induced hepatotoxicity.

References

  • 1. Jain D. Cardiotoxicity of doxorubicin and other anthracycline derivatives. J Nucl Cardiol. 2000;7(1): 53-62. doi: 10.1067/mnc.2000.103324.
  • 2. Gabizon AA, Patil Y, and La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016;29:90-106. doi: 10.1016/j.drup.2016.10.003.
  • 3. Naziroglu M, Oz A, Yildizhan K. Selenium and Neurological Diseases: Focus on Peripheral Pain and TRP Channels. Curr Neuropharmacol. 2020;18(6):501-17. doi: 10.2174/1570159X18666200106152631.
  • 4. Reich HJ and Hondal RJ. Why nature chose selenium. ACS Chem Biol. 2016;11(4):821-41. doi: 10.1021/acschembio.6b00031.
  • 5. Solovyev ND. Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signalling. J Inorg Biochem. 2015;153:1-12. doi: 10.1016/j.jinorgbio.2015.09.003.
  • 6. Ali ES, Rychkov GY, Barritt GJ. TRPM2 non-selective cation channels in liver injury mediated by reactive oxygen species. Antioxidants (Basel). 2021;10(8):1243. doi: 10.3390/antiox10081243.
  • 7. Malko P, Jiang LH. TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol. 2020;37:101755. doi: 10.1016/j.redox.2020.101755.
  • 8. Çınar R, Nazıroğlu M. TRPM2 Channel Inhibition Attenuates Amyloid β42-Induced Apoptosis and Oxidative Stress in the Hippocampus of Mice. Cell Mol Neurobiol. 2023;43(3):1335-53. doi: 10.1007/s10571-022-01253-0.
  • 9. Nakai H, Konno M, Kosuge S, et al. New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships. J Med Chem. 1988;31(1):84-91. doi: 10.1021/jm00396a013.
  • 10. Yazğan B, Yazğan Y. Regulatory role of phospholipase A2 inhibitor in oxidative stress and inflammation induced by an experimental mouse migraine model. J Cell Neurosci Oxid Stress. 2023;15(2):1147-56. doi: 10.37212/jcnos.1365512.
  • 11. Hassan MQ, Akhtar MS, Afzal O, et al. Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity. Clin Exp Hypertens. 2020;42(5):381-92. doi: 10.1080/10641963.2019.1676770.
  • 12. Cengiz O, Baran M, Balcioglu E, et al. Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem. 2021;96(1):67-75. doi: 10.1080/10520295.2020.1760353.
  • 13. Cakir M, Duzova H, Tekin S, et al. ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. Life Sci. 2017;176:10-20. doi: 10.1016/j.lfs.2017.03.022.
  • 14. Uçar B, Huyut Z, Altındağ F, et al. Relationship with nephrotoxicity of Abemaciclib in rats: Protective effect of Curcumin. Indian J Biochem Biophys. 2022;59:963-76. doi: 10.56042/ijbb.v59i10.64336.
  • 15. Gyulkhasyan T, Hakobyan T, Parikh A, et al. Doxorubicin‐induced cardiomyopathy: Prevention and treatment by a coronary specific vasodilator. The FASEB Journal. 2019;33(S1):685.14-685.14. doi: 10.1096/fasebj.2019.33.1_supplement.685.14.
  • 16. Ahsan U, Kamran Z, Raza I, et al. Role of selenium in male reproduction—A review. Anim Reprod Sci. 2014;146(1-2):55-62. doi: 10.1016/j.anireprosci.2014.01.009.
  • 17. Kheradpezhouh E, Ma L, Morphett A, et al. TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci U S A. 2014;111(8):3176-81. doi: 10.1073/pnas.1322657111.
  • 18. Singla S, Kumar NR, Kaur J. In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats. Toxicol Int. 2014;21(2):191-5. doi: 10.4103/0971-6580.139808.
  • 19. Kuzu M, Yıldırım S, Kandemir FM, et al. Protective effect of morin on doxorubicin-induced hepatorenal toxicity in rats. Chem Biol Interact. 2019;308:89-100. doi: 10.1016/j.cbi.2019.05.017.
  • 20. Wali AF, Rashid S, Rashid SM, et al. Naringenin regulates doxorubicin-induced liver dysfunction: impact on oxidative stress and inflammation. Plants (Basel). 2020;9(4):550. doi: 10.3390/plants9040550.
  • 21. Bilgic S, Ozgocmen M. The protective effect of misoprostol against doxorubicin induced liver injury. Biotech Histochem. 2019;94(8):583-91. doi: 10.1080/10520295.2019.1605457.
  • 22. Zhang T, Huang W, Ma Y. Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway. Int Immunopharmacol. 2022;104:108443. doi: 10.1016/j.intimp.2021.108443.
  • 23. Shokrzadeh M, Bagheri A, Ghassemi-Barghi N, et al. Doxorubicin and doxorubicin-loaded nanoliposome induce senescence by enhancing oxidative stress, hepatotoxicity, and in vivo genotoxicity in male Wistar rats. Naunyn Schmiedeberg's Arch Pharmacol. 2021;394(8):1803-13. doi: 10.1007/s00210-021-02119-w.
  • 24. Khan MA, Singh D, Arif A, et al. Protective effect of green synthesized Selenium Nanoparticles against Doxorubicin induced multiple adverse effects in Swiss albino mice. Life Sci. 2022;305:120792. doi: 10.1016/j.lfs.2022.120792.
  • 25. Belhan S, Özkaraca M, Özdek U, et al. Protective role of chrysin on doxorubicin‐induced oxidative stress and DNA damage in rat testes. Andrologia. 2020;52(9):e13747. doi: 10.1111/and.13747.

Doksorubisin kaynaklı karaciğer hasarında oksidatif stres, apoptoz ve değişen TRPM2 kanalı aktivasyonunun rolü; selenyumun koruyucu etkisi

Year 2024, Volume: 8 Issue: 2, 118 - 124, 30.08.2024
https://doi.org/10.30565/medalanya.1483307

Abstract

Amaç: Doksorubisin (DOXR) çeşitli kanser türlerinin tedavisinde sıklıkla tek başına veya kombinasyon terapisi olarak kullanılmaktadır.doza bağlı olarak değişen yan etkiler bilinmesine rağmen, karaciğer sağlığı üzerindeki etkileri tam olarak bilinmemektedir. Bu araştırma, DOXR ile tedavi edilen sıçanlarda geçici reseptör potansiyeli melastatin-2 (TRPM2) kanalının rolünü, TRPM-2 kanal blokörü N-(p-amilsinamoil) antranilik asit (ACA) kullanarak araştırmayı ve selenyum (Se)'un koruycu etkilerini araştırmayı amaçladı.

Yöntemler: Sıçanlar altı gruba ayrıldı (n=10): kontrol, DMSO, DOXR, DOXR + Se, DOXR + ACA ve DOXR + ACA + Se. Serum AST, ALT, LDH, trigliserit ve total kolesterol seviyeleri ölçüldü. Ayrıca, karaciğer dokusunda TRPM2 kanalı, 8-OHdG ve kaspaz-3 (Casp-3) ekspresyonları için immünohistokimyasal testler ve ayrıca histopatolojik değerlendirme yapıldı.

Bulgular: Serum AST, ALT, LDH, trigliserid ve total kolesterol seviyeleri ve ayrıca karaciğer 8-OHdG, TRPM2 kanalı ve Casp-3 ekspresyonları DOXR grubunda DOXR + Se, DOXR + ACA ve DOXR + ACA + Se gruplarına göre anlamlı derecede yüksekti (p <0.05). Ancak, bu parametreler Se ve ACA ile tedavi edilen gruplarda DOXR grubuna kıyasla önemli ölçüde düşmüştü (p <0.05).

Sonuç: Sonuçlar, Se veya ACA'nın DOXR ile eşzamanlı uygulanmasının, DOXR kaynaklı hepatotoksisiteyle mücadelede etkili bir terapötik yaklaşım sağlayabileceğini göstermektedir.

References

  • 1. Jain D. Cardiotoxicity of doxorubicin and other anthracycline derivatives. J Nucl Cardiol. 2000;7(1): 53-62. doi: 10.1067/mnc.2000.103324.
  • 2. Gabizon AA, Patil Y, and La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016;29:90-106. doi: 10.1016/j.drup.2016.10.003.
  • 3. Naziroglu M, Oz A, Yildizhan K. Selenium and Neurological Diseases: Focus on Peripheral Pain and TRP Channels. Curr Neuropharmacol. 2020;18(6):501-17. doi: 10.2174/1570159X18666200106152631.
  • 4. Reich HJ and Hondal RJ. Why nature chose selenium. ACS Chem Biol. 2016;11(4):821-41. doi: 10.1021/acschembio.6b00031.
  • 5. Solovyev ND. Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signalling. J Inorg Biochem. 2015;153:1-12. doi: 10.1016/j.jinorgbio.2015.09.003.
  • 6. Ali ES, Rychkov GY, Barritt GJ. TRPM2 non-selective cation channels in liver injury mediated by reactive oxygen species. Antioxidants (Basel). 2021;10(8):1243. doi: 10.3390/antiox10081243.
  • 7. Malko P, Jiang LH. TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol. 2020;37:101755. doi: 10.1016/j.redox.2020.101755.
  • 8. Çınar R, Nazıroğlu M. TRPM2 Channel Inhibition Attenuates Amyloid β42-Induced Apoptosis and Oxidative Stress in the Hippocampus of Mice. Cell Mol Neurobiol. 2023;43(3):1335-53. doi: 10.1007/s10571-022-01253-0.
  • 9. Nakai H, Konno M, Kosuge S, et al. New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships. J Med Chem. 1988;31(1):84-91. doi: 10.1021/jm00396a013.
  • 10. Yazğan B, Yazğan Y. Regulatory role of phospholipase A2 inhibitor in oxidative stress and inflammation induced by an experimental mouse migraine model. J Cell Neurosci Oxid Stress. 2023;15(2):1147-56. doi: 10.37212/jcnos.1365512.
  • 11. Hassan MQ, Akhtar MS, Afzal O, et al. Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity. Clin Exp Hypertens. 2020;42(5):381-92. doi: 10.1080/10641963.2019.1676770.
  • 12. Cengiz O, Baran M, Balcioglu E, et al. Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem. 2021;96(1):67-75. doi: 10.1080/10520295.2020.1760353.
  • 13. Cakir M, Duzova H, Tekin S, et al. ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. Life Sci. 2017;176:10-20. doi: 10.1016/j.lfs.2017.03.022.
  • 14. Uçar B, Huyut Z, Altındağ F, et al. Relationship with nephrotoxicity of Abemaciclib in rats: Protective effect of Curcumin. Indian J Biochem Biophys. 2022;59:963-76. doi: 10.56042/ijbb.v59i10.64336.
  • 15. Gyulkhasyan T, Hakobyan T, Parikh A, et al. Doxorubicin‐induced cardiomyopathy: Prevention and treatment by a coronary specific vasodilator. The FASEB Journal. 2019;33(S1):685.14-685.14. doi: 10.1096/fasebj.2019.33.1_supplement.685.14.
  • 16. Ahsan U, Kamran Z, Raza I, et al. Role of selenium in male reproduction—A review. Anim Reprod Sci. 2014;146(1-2):55-62. doi: 10.1016/j.anireprosci.2014.01.009.
  • 17. Kheradpezhouh E, Ma L, Morphett A, et al. TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci U S A. 2014;111(8):3176-81. doi: 10.1073/pnas.1322657111.
  • 18. Singla S, Kumar NR, Kaur J. In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats. Toxicol Int. 2014;21(2):191-5. doi: 10.4103/0971-6580.139808.
  • 19. Kuzu M, Yıldırım S, Kandemir FM, et al. Protective effect of morin on doxorubicin-induced hepatorenal toxicity in rats. Chem Biol Interact. 2019;308:89-100. doi: 10.1016/j.cbi.2019.05.017.
  • 20. Wali AF, Rashid S, Rashid SM, et al. Naringenin regulates doxorubicin-induced liver dysfunction: impact on oxidative stress and inflammation. Plants (Basel). 2020;9(4):550. doi: 10.3390/plants9040550.
  • 21. Bilgic S, Ozgocmen M. The protective effect of misoprostol against doxorubicin induced liver injury. Biotech Histochem. 2019;94(8):583-91. doi: 10.1080/10520295.2019.1605457.
  • 22. Zhang T, Huang W, Ma Y. Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway. Int Immunopharmacol. 2022;104:108443. doi: 10.1016/j.intimp.2021.108443.
  • 23. Shokrzadeh M, Bagheri A, Ghassemi-Barghi N, et al. Doxorubicin and doxorubicin-loaded nanoliposome induce senescence by enhancing oxidative stress, hepatotoxicity, and in vivo genotoxicity in male Wistar rats. Naunyn Schmiedeberg's Arch Pharmacol. 2021;394(8):1803-13. doi: 10.1007/s00210-021-02119-w.
  • 24. Khan MA, Singh D, Arif A, et al. Protective effect of green synthesized Selenium Nanoparticles against Doxorubicin induced multiple adverse effects in Swiss albino mice. Life Sci. 2022;305:120792. doi: 10.1016/j.lfs.2022.120792.
  • 25. Belhan S, Özkaraca M, Özdek U, et al. Protective role of chrysin on doxorubicin‐induced oxidative stress and DNA damage in rat testes. Andrologia. 2020;52(9):e13747. doi: 10.1111/and.13747.
There are 25 citations in total.

Details

Primary Language English
Subjects Clinical Sciences (Other)
Journal Section Research Article
Authors

Kenan Yıldızhan 0000-0002-6585-4010

Zübeyir Huyut 0000-0002-7623-1492

Fikret Altındağ 0000-0002-7085-623X

Mehmet Hafit Bayir 0000-0001-5821-4560

Publication Date August 30, 2024
Submission Date May 14, 2024
Acceptance Date July 30, 2024
Published in Issue Year 2024 Volume: 8 Issue: 2

Cite

Vancouver Yıldızhan K, Huyut Z, Altındağ F, Bayir MH. The role of oxidative stress, apoptosis and altered TRPM2 channel activation in doxorubicin-induced liver injury; the protective effect of selenium. Acta Med. Alanya. 2024;8(2):118-24.

9705

This Journal is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.