Molecular Cardiotoxic Effects of Proteasome Inhibitors Carfilzomib and Ixazomib and Their Combination with Dexamethasone Involve Mitochondrial Dysregulation

by Selleckchem | Mar 16 2023

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.

Comments：

The study investigated the molecular cardiotoxic mechanisms of two proteasome inhibitors, carfilzomib (CFZ) and ixazomib (IXZ), alone or in combination with the immunomodulatory drug dexamethasone (DEX), in a cardiomyocyte model. The findings suggest that the cardiotoxicity of proteasome inhibitors may be due to their class effect and involve stress response and mitochondrial dysfunction.

The study found that CFZ showed a higher cytotoxic effect than IXZ at lower concentrations. The DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused an increase in K48 ubiquitination, which is associated with proteasome dysfunction and ER stress. Both CFZ and IXZ caused an upregulation in cellular and ER stress protein levels, including HSP90, HSP70, GRP94, and GRP78. The DEX combination attenuated the increased stress protein levels.

The study also found that 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.

Overall, the study suggests that proteasome inhibitors may cause cardiotoxicity through a class effect involving stress response and mitochondrial dysfunction. The findings highlight the need for further studies to understand the cardiotoxicity of proteasome inhibitors and to develop strategies to minimize their side effects.