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İmatinib Mesilat Kaynaklı Kardiyo-Toksisitede Astaksantinin Etkileri

Year 2020, Volume: 4 Issue: 1, 68 - 75, 02.03.2020

Abstract

Amaç: Imatinib mesilat bir tirozin kinaz inhibitörüdür ve kronik miyeloid löseminin standart bir birinci basamak tedavisi olarak onaylanmıştır. Kemoterapiye bağlı kardiyotoksisitede oksidatif stresin yanı sıra hücre içi kalsiyum aşırı yüklenmesi ve mitokondriyal disfonksiyon önemli rol oynar. İmatinib ile indüklenen kardiyotoksisitenin neden olduğu altta yatan patofizyolojik mekanizma tam olarak anlaşılamamıştır. Bu çalışmada, geçici reseptör potansiyel melastatin 2 (TRPM2) kanalları üzerinden kalsiyum akışı, oksidatif stres ve apoptozdaki değişimleri araştırdık. Ayrıca, imatinib mesilat kaynaklı kardiyotoksisite sırasında astaksantinin kardiyomiyositlerde modülatör rolü olup olmadığını araştırdık.

Gereç ve yöntemler: Hücreler, kontrol, imatinib, imatinib + antranilik asit, imatinib + astaksantin, imatinib + antranilik asit + astaksantin, astaksantin ve astaksantin + antranilik asit grupları olmak üzere yedi ana gruba ayrıldı. Gruplardaki hücreler, ilgili deneylerde TRPM2 kanallarının aktivasyonu ve inaktivasyonu için sırasıyla kümen hidroperoksit ile uyarıldı ve antranilik asit ile inhibe edildi. Sitosolik kalsiyum, hücre içi reaktif oksijen, mitokondriyal depolarizasyon, kaspaz 3 ve kaspaz 9 seviyeleri ölçüldü.

Bulgular: Apoptoz değerleri astaksantin ve imatinib + astaksantin grubunda, imatinib grubundaki kardiyomiyositlerden anlamlı olarak daha düşüktü (p<0.001). Hücre canlılığı değerleri imatinib + astaksantin + antranilik asit (p<0.001) ve imatinib + astaksantin (p <0.05) gruplarında imatinib grubundan anlamlı olarak daha yüksekti.

Sonuç: Sonuç olarak, TRPM2 kanallarının kardiyomiyosit hücrelerinde bulunduğunu ve reaktif oksijen türleri ile aktive edildiğini bulduk. Ayrıca, aşırı aktifleştirilmiş TRPM2 kanallarının, imatinib mesilat ile indüklenen kardiyotoksisitede artmış sitosolik serbest kalsiyum, oksidatif stres ve apoptotik hücre hasarı ile ilişkili olduğunu, buna karşın astaksantinin bu aşamada modülatör bir rol oynayabileceğini gösterdik.

References

  • 1. Van Etten RA. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res. 2004;28(suppl 1):21-8. PMID: 15036938
  • 2. Fausel C. Targeted chronic myeloid leukemia therapy: Seeking a cure. Am J Health Syst Pharm. 2007;64:S9-15. PMID: 18056932
  • 3. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-16. PMID: 16862153
  • 4. Turrisi G, Montagnani F, Grotti S, et al. Congestive heart failure during imatinib mesylate treatment. Int J Cardiol. 2010;145:148-50. PMID: 19656583
  • 5. Varga ZV, Ferdinandy P, Liaudet L, et al. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol. 2015;309:H1453-67. PMID: 26386112
  • 6. Fassett RG, Coombes JS. Astaxanthin: a potential therapeutic agent in cardiovascular disease. Marine Drugs. 2011;9:447-65. PMID: 21556169
  • 7. Martinez NA, Ayala AM, Martinez M, et al. Caveolin-1 regulates the P2Y2 receptor signaling in human 1321N1 astrocytoma cells. J Biol Chem. 2016;291:12208-22. PMID: 27129210
  • 8. Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes. 2011;2:82-91. PMID: 21860691
  • 9. Özdemir ÜS, Nazıroğlu M, Şenol N, et al. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol. 2016;53:3540-51. PMID: 26099309
  • 10. Bejarano I, Redondo PC, Espino J, et al. Melatonin induces mitochondrial‐mediated apoptosis in human myeloid HL‐60 cells. J Pineal Res. 2009;46:392-400. PMID: 19552762
  • 11. Uguz AC, Cig B, Espino J, et al. Melatonin potentiates chemotherapy‐induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res. 2012;53:91-8. PMID: 22288984
  • 12. Övey I, Naziroğlu M. Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. Neuroscience. 2015;284:225-33. PMID: 25305668
  • 13. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640-53. PMID: 15618470
  • 14. Perik P, Rikhof B, De Jong F, et al. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol. 2007;19:359-61. PMID: 17962203
  • 15. Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935-42. PMID: 12006504
  • 16. Thanopoulou E, Judson I. The safety profile of imatinib in CML and GIST: long-term considerations. Arch Toxicol. 2012;86:1-12. PMID: 21717109
  • 17. Maharsy W, Aries A, Mansour O, et al. Ageing is a risk factor in imatinib mesylate cardiotoxicity. Eur J Heart Fail. 2014;16:367-76. PMID: 24504921
  • 18. Wouters KA, Kremer L, Miller TL, et al. Protecting against anthracycline‐induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005;131:561-78. PMID: 16351632
  • 19. Flemming NB, Gallo LA, Forbes JM. Mitochondrial Dysfunction and Signaling in Diabetic Kidney Disease: Oxidative Stress and Beyond. Semin Nephrol. 2018;38:101-10. PMID: 29602393
  • 20. Barr LA, Makarewich CA, Berretta RM, et al. Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. Clin Transl Sci. 2014;7:360-7. PMID: 24931551
  • 21. Fliniaux I, Germain E, Farfariello V, et al. TRPs and Ca2+ in cell death and survival. Cell Calcium. 2018;69:4-18. PMID: 28760561
  • 22. Zhan KY, Yu PL, Liu CH, et al. Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury. Acta Pharmacol Sin. 2016;37:4-12. PMID: 26725732
  • 23. Sumoza‐Toledo A, Penner R. TRPM2: a multifunctional ion channel for calcium signaling. J Physiol. 2011;589:1515-25. PMID: 21135052
  • 24. Wang Q, Huang L, Yue J. Oxidative stress activates the TRPM2-Ca2+CaMKII-ROS signaling loop to induce cell death in cancer cells. Biochim Biophys Acta. 2017;1864:957-67. PMID: 28007458
  • 25. Hoffman NE, Miller BA, Wang J, et al. Ca 2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am J Physiol Heart Circ Physiol. 2015;308:H637-50. PMID: 25576627
  • 26. Yang K, Chang W, Yang P, et al. Activation of the transient receptor potential M2 channel and poly (ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death Differ. 2006;13:1815-26. PMID: 16294211
  • 27. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213-23. PMID: 17592090
  • 28. Sagiroglu T, Kanter M, Yagci MA et al. Protective effect of curcumin on cyclosporin A-induced endothelial dysfunction, antioxidant capacity, and oxidative damage. Toxicol Ind Health. 2014;30:316-27. PMID: 22903178
  • 29. Ekeløf S, Jensen SE, Rosenberg J et al. Reduced oxidative stress in STEMI patients treated by primary percutaneous coronary intervention and with antioxidant therapy: a systematic review. Cardiovasc Drugs Ther. 2014;28:173-81. PMID: 24532094
  • 30. Fassett RG, Coombes JS. Astaxanthin in cardiovascular health and disease. Molecules. 2012;17:2030-48. PMID: 22349894

Effect of astaxanthin in imatinib mesylate-induced cardiotoxicity

Year 2020, Volume: 4 Issue: 1, 68 - 75, 02.03.2020

Abstract

Aim: Imatinib mesylate is a tyrosine kinase inhibitor and is approved as a standard first-line therapy of chronic myeloid leukemia. Oxidative stress, as well as intracellular calcium overload and mitochondrial dysfunction, play an important role in chemotherapy-induced cardiotoxicity. The underlying pathophysiological mechanism associated with imatinib-induced cardiotoxicity is not well understood. In the present study, we investigated alterations in calcium influx, oxidative stress and apoptosis through transient receptor potential melastatin 2 (TRPM2) channels. Also, we aimed to investigate if there is a modulator role of astaxanthin in cardiomyocytes during imatinib mesylate-induced cardiotoxicity.

Materials and methods: The cells were divided into seven main control groups: imatinib, imatinib+antranilic acid, imatinib+astaxanthin, imatinib+antranilic acid+astaxanthin, astaxanthin and astaxanthin+antranilic acid groups. Cells in the groups were stimulated with cumene hydroperoxide and inhibited with antranilic acid in related experiments for activation and inactivation of TRPM2 channels, respectively. We measured cytosolic calcium, intracellular reactive oxygene, mitochondrial depolarization, caspase 3 and caspase 9 levels.

Results: The apoptosis values were significantly lower in the astaxanthin and the imatinib+astaxanthin group than in the imatinib group of cardiomyocytes (p< 0.001). The cell viability values were significantly higher in the imatinib+astaxanthin+antranilic acid (p<0.001) and the imatinib+astaxanthin (p<0.05) groups, than in the imatinib group.

Conclusions: As a result, we found that TRPM2 channels were found in cardiomyocyte cells and they were activated by reactive oxygen species. Also, we showed that overactivated TRPM2 channels are associated with increased cytosolic free calcium, oxidative stress and apoptotic cell injury in imatinib mesylate-induced cardiotoxicity, whereas astaxanthin could have a modulator role in this instance.

References

  • 1. Van Etten RA. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res. 2004;28(suppl 1):21-8. PMID: 15036938
  • 2. Fausel C. Targeted chronic myeloid leukemia therapy: Seeking a cure. Am J Health Syst Pharm. 2007;64:S9-15. PMID: 18056932
  • 3. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-16. PMID: 16862153
  • 4. Turrisi G, Montagnani F, Grotti S, et al. Congestive heart failure during imatinib mesylate treatment. Int J Cardiol. 2010;145:148-50. PMID: 19656583
  • 5. Varga ZV, Ferdinandy P, Liaudet L, et al. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol. 2015;309:H1453-67. PMID: 26386112
  • 6. Fassett RG, Coombes JS. Astaxanthin: a potential therapeutic agent in cardiovascular disease. Marine Drugs. 2011;9:447-65. PMID: 21556169
  • 7. Martinez NA, Ayala AM, Martinez M, et al. Caveolin-1 regulates the P2Y2 receptor signaling in human 1321N1 astrocytoma cells. J Biol Chem. 2016;291:12208-22. PMID: 27129210
  • 8. Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes. 2011;2:82-91. PMID: 21860691
  • 9. Özdemir ÜS, Nazıroğlu M, Şenol N, et al. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol. 2016;53:3540-51. PMID: 26099309
  • 10. Bejarano I, Redondo PC, Espino J, et al. Melatonin induces mitochondrial‐mediated apoptosis in human myeloid HL‐60 cells. J Pineal Res. 2009;46:392-400. PMID: 19552762
  • 11. Uguz AC, Cig B, Espino J, et al. Melatonin potentiates chemotherapy‐induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res. 2012;53:91-8. PMID: 22288984
  • 12. Övey I, Naziroğlu M. Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. Neuroscience. 2015;284:225-33. PMID: 25305668
  • 13. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640-53. PMID: 15618470
  • 14. Perik P, Rikhof B, De Jong F, et al. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol. 2007;19:359-61. PMID: 17962203
  • 15. Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935-42. PMID: 12006504
  • 16. Thanopoulou E, Judson I. The safety profile of imatinib in CML and GIST: long-term considerations. Arch Toxicol. 2012;86:1-12. PMID: 21717109
  • 17. Maharsy W, Aries A, Mansour O, et al. Ageing is a risk factor in imatinib mesylate cardiotoxicity. Eur J Heart Fail. 2014;16:367-76. PMID: 24504921
  • 18. Wouters KA, Kremer L, Miller TL, et al. Protecting against anthracycline‐induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005;131:561-78. PMID: 16351632
  • 19. Flemming NB, Gallo LA, Forbes JM. Mitochondrial Dysfunction and Signaling in Diabetic Kidney Disease: Oxidative Stress and Beyond. Semin Nephrol. 2018;38:101-10. PMID: 29602393
  • 20. Barr LA, Makarewich CA, Berretta RM, et al. Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. Clin Transl Sci. 2014;7:360-7. PMID: 24931551
  • 21. Fliniaux I, Germain E, Farfariello V, et al. TRPs and Ca2+ in cell death and survival. Cell Calcium. 2018;69:4-18. PMID: 28760561
  • 22. Zhan KY, Yu PL, Liu CH, et al. Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury. Acta Pharmacol Sin. 2016;37:4-12. PMID: 26725732
  • 23. Sumoza‐Toledo A, Penner R. TRPM2: a multifunctional ion channel for calcium signaling. J Physiol. 2011;589:1515-25. PMID: 21135052
  • 24. Wang Q, Huang L, Yue J. Oxidative stress activates the TRPM2-Ca2+CaMKII-ROS signaling loop to induce cell death in cancer cells. Biochim Biophys Acta. 2017;1864:957-67. PMID: 28007458
  • 25. Hoffman NE, Miller BA, Wang J, et al. Ca 2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am J Physiol Heart Circ Physiol. 2015;308:H637-50. PMID: 25576627
  • 26. Yang K, Chang W, Yang P, et al. Activation of the transient receptor potential M2 channel and poly (ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death Differ. 2006;13:1815-26. PMID: 16294211
  • 27. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213-23. PMID: 17592090
  • 28. Sagiroglu T, Kanter M, Yagci MA et al. Protective effect of curcumin on cyclosporin A-induced endothelial dysfunction, antioxidant capacity, and oxidative damage. Toxicol Ind Health. 2014;30:316-27. PMID: 22903178
  • 29. Ekeløf S, Jensen SE, Rosenberg J et al. Reduced oxidative stress in STEMI patients treated by primary percutaneous coronary intervention and with antioxidant therapy: a systematic review. Cardiovasc Drugs Ther. 2014;28:173-81. PMID: 24532094
  • 30. Fassett RG, Coombes JS. Astaxanthin in cardiovascular health and disease. Molecules. 2012;17:2030-48. PMID: 22349894
There are 30 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Article
Authors

İshak Suat Övey 0000-0002-0392-4386

Can Ramazan Öncel 0000-0001-5422-6847

Publication Date March 2, 2020
Submission Date August 2, 2019
Acceptance Date October 8, 2019
Published in Issue Year 2020 Volume: 4 Issue: 1

Cite

Vancouver Övey İS, Öncel CR. Effect of astaxanthin in imatinib mesylate-induced cardiotoxicity. Acta Med. Alanya. 2020;4(1):68-75.

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