Jannuzzi Ayse Tarbin, Korkmaz Nalan Sümeyra, Gunaydin Akyildiz Aysenur, Arslan Eseryel Sema, Karademir Yilmaz Betul, Alpertunga Buket
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey.
Cardiovasc Toxicol. 2023 Apr;23(3-4):121-131. doi: 10.1007/s12012-023-09785-7. Epub 2023 Feb 21.
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.
随着新型蛋白酶体抑制剂的研发和获批，蛋白酶体抑制在癌症治疗中越来越受到认可。除了在血液系统癌症中取得成功的抗癌效果外，诸如心脏毒性等副作用限制了有效治疗。在本研究中，我们使用心肌细胞模型来研究卡非佐米（CFZ）和伊沙佐米（IXZ）单独使用或与免疫调节药物地塞米松（DEX）联合使用时的分子心脏毒性机制，地塞米松在临床联合治疗中经常使用。根据我们的研究结果，CFZ在较低浓度下比IXZ表现出更高的细胞毒性作用。DEX联合用药减弱了两种蛋白酶体抑制剂的细胞毒性。所有药物处理均导致K48泛素化显著增加。CFZ和IXZ均导致细胞和内质网应激蛋白（HSP90、HSP70、GRP94和GRP78）水平上调，而DEX联合用药减弱了应激蛋白水平的升高。重要的是，IXZ和IXZ - DEX处理导致的线粒体分裂和融合基因表达水平上调高于CFZ和CFZ - DEX联合处理。IXZ - DEX联合用药比CFZ - DEX联合用药更能降低氧化磷酸化蛋白（复合物II - V）的水平。在心肌细胞中，所有药物处理均检测到线粒体膜电位降低和ATP生成减少。我们的研究结果表明，蛋白酶体抑制剂的心脏毒性作用可能归因于它们的类效应和应激反应，线粒体功能障碍可能参与了心脏毒性过程。
