Molecular cardiotoxic effects of proteasome inhibitors Carfilzomib and Ixazomib and their combination with dexamethasone involve mitochondrial dysregulation
Yükleniyor...
Tarih
2023
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Humana Press
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
With the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic. According to our findings, CFZ showed a higher cytotoxic effect at lower concentrations than IXZ. DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused a marked increase in K48 ubiquitination. Both CFZ and IXZ caused an upregulation in cellular and endoplasmic reticulum stress protein (HSP90, HSP70, GRP94, and GRP78) levels and DEX combination attenuated the increased stress protein levels. Importantly, IXZ and IXZ-DEX treatments caused upregulation of mitochondria fission and fusion gene expression levels higher than caused by CFZ and CFZ-DEX combination. The IXZ-DEX combination reduced the levels of OXPHOS proteins (Complex II-V) more than the CFZ-DEX combination. Reduced mitochondrial membrane potential and ATP production were detected with all drug treatments in cardiomyocytes. Our findings suggest that the cardiotoxic effect of proteasome inhibitors may be due to their class effect and stress response and mitochondrial dysfunction may be involved in the cardiotoxicity process.
Açıklama
Anahtar Kelimeler
Cardiotoxicity, Mitochondrial Toxicity, Proteasome Inhibitors, Stress Response
Kaynak
Cardiovascular Toxicology
WoS Q Değeri
Q2
Scopus Q Değeri
Q2
Cilt
23
Sayı
3-4
Künye
Jannuzzi, A. T., Korkmaz, N. S., Günaydın-Akyıldız, A., Arslan Eseryel, S., Karademir Yılmaz, B., & Alpertunga, B. (2023). Molecular cardiotoxic effects of proteasome inhibitors Carfilzomib and Ixazomib and their combination with dexamethasone involve mitochondrial dysregulation. Cardiovascular Toxicology, 23(3-4), 121-131.
https://doi.org/10.1007/s12012-023-09785-7
