İmatinib Mesilat Kaynaklı Kardiyo-Toksisitede Astaksantinin Etkileri

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

İshak Suat Övey , Can Ramazan Öncel

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.

Keywords

İmatinib mesylate, TRPM2, oksidatif stres, kardiyomyosit

Effect of astaxanthin in imatinib mesylate-induced cardiotoxicity

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.

Keywords

İmatinib mesylate, TRPM2, oxidative stress, cardiomyocyte

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