Refaie Marwa M M, Shehata Sayed, Bayoumi Asmaa M A, El-Tahawy Nashwa Fathy Gamal, Abdelzaher Walaa Yehia
Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt.
Department of Cardiology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt.
Cardiovasc Drugs Ther. 2022 Oct;36(5):817-827. doi: 10.1007/s10557-021-07214-x. Epub 2021 Jun 29.
The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it.
We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day.
The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties.
FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.
5-氟尿嘧啶（5FU）等抗癌药物的心脏毒性是一个主要并发症，对其临床应用构成挑战。因此，迫切需要找到新的保护药物来抵御这些有害副作用。到目前为止，尚无研究评估非诺贝特（FEN）对5FU诱导的心脏毒性可能具有的心脏保护作用。因此，在当前模型中，我们旨在评估FEN的这种作用，并探索介导该作用的不同机制。
我们使用FEN（25、50、100毫克/千克/天）口服给药7天，并在第5天通过腹腔注射5FU（150毫克/千克）诱导心脏毒性。
当前研究表明，5FU成功诱导了心脏毒性，表现为心脏酶、组织丙二醛（MDA）、白细胞介素6（IL-6）、信号转导和转录激活因子4（STAT4）以及半胱天冬酶-3水平显著升高。此外，5FU组显示出毒性组织病理学变化，包括明显的心脏损伤以及还原型谷胱甘肽（GSH）、总抗氧化能力（TAC）和过氧化物酶体增殖物激活受体α（PPARα）表达显著降低。FEN通过多种机制逆转了5FU诱导的心脏毒性，这些机制包括上调PPARα、抑制IL-6/STAT信号通路以及抗炎、抗凋亡和抗氧化特性。
FEN对5FU诱导的心脏损伤具有显著的心脏保护作用。
