Sheta A, Elsakkar M, Hamza M, Solaiman A
1 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
2 Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Hum Exp Toxicol. 2016 Nov;35(11):1227-1239. doi: 10.1177/0960327115627685. Epub 2016 Jul 11.
The use of doxorubicin (DOX) as an antitumor therapeutic agent is limited due to its cardiotoxic effects. Metformin (Met) and sitagliptin (Sitg) are suggested to improve cardiac function. The present study aimed to determine the potential protective effects of Met and Sitg on DOX-induced cardiotoxicity. Rats were divided into six groups: groups I, II, and III received normal saline, Met, and Sitg, respectively. Groups IV, V, and VI received DOX only, Met + DOX, and Sitg + DOX, respectively. Heart tissue was used for biochemical assays which measured cardiac reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and tumor necrosis factor α (TNF-α). Serum creatinine kinase (CK) and lactate dehydrogenase (LDH) were also measured. The heart apex was prepared for histological (hematoxylin and eosin) and immunohistochemical examination. Intoxication of DOX was associated with a significant elevation in serum CK-MB and LDH, reduction in cardiac GSH, and increased TBARS and TNF-α compared to the controls. Administration of Met or Sitg to DOX-intoxicated rats suppressed serum CK-MB and LDH. Moreover, cardiac GSH was elevated with decreased TBARS and TNF-α. These results were confirmed by histological study. Met and Sitg caused inhibition of caspase 3 and upregulation of B-cell lymphoma 2 (Bcl-2) expression in DOX-intoxicated animals. Sitg was found to exert a significantly better protective effect compared to that of Met. It was concluded that Sitg might be more effective than Met in reducing myocardial injury in DOX-induced cardiotoxicity in rats.
由于阿霉素（DOX）具有心脏毒性作用，其作为抗肿瘤治疗药物的应用受到限制。二甲双胍（Met）和西他列汀（Sitg）被认为可改善心脏功能。本研究旨在确定Met和Sitg对DOX诱导的心脏毒性的潜在保护作用。将大鼠分为六组：第一、二、三组分别接受生理盐水、Met和Sitg。第四、五、六组分别仅接受DOX、Met + DOX和Sitg + DOX。心脏组织用于生化检测，测量心脏还原型谷胱甘肽（GSH）、硫代巴比妥酸反应性物质（TBARS）和肿瘤坏死因子α（TNF-α）。还测量了血清肌酐激酶（CK）和乳酸脱氢酶（LDH）。取心脏尖部进行组织学（苏木精和伊红）和免疫组织化学检查。与对照组相比，DOX中毒与血清CK-MB和LDH显著升高、心脏GSH降低以及TBARS和TNF-α增加有关。给DOX中毒的大鼠施用Met或Sitg可抑制血清CK-MB和LDH。此外，心脏GSH升高，同时TBARS和TNF-α降低。这些结果通过组织学研究得到证实。Met和Sitg在DOX中毒的动物中引起半胱天冬酶3的抑制和B细胞淋巴瘤2（Bcl-2）表达的上调。发现Sitg比Met具有明显更好的保护作用。得出的结论是，在减轻大鼠DOX诱导的心脏毒性中的心肌损伤方面，Sitg可能比Met更有效。
