A Chemosensitizer Drug: Disulfiram Prevents Doxorubicin-Induced Cardiac Dysfunction and Oxidative Stress in Rats
A Chemosensitizer Drug: Disulfiram Prevents Doxorubicin-Induced Cardiac Dysfunction and Oxidative Stress in Rats
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DOI：
10.1007/s12012-018-9458-y
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发表时间：
2018-10-01
影响因子：
3.2
通讯作者：
Patil, Chandragouda R.
中科院分区：
文献类型：
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作者：
Sonawane, Varsha K.;Mahajan, Umesh B.;Patil, Chandragouda R.
在本研究中，口服双硫仑（DS）对阿霉素（DOX）诱导的大鼠心脏毒性的预防作用进行了研究。DS以2、10和50 mg/kg/天的剂量经口给药7天。在开始DS治疗的第5天，腹腔内给予DOX（30 mg/kg）。在注射后48小时内，DOX治疗显著改变了ECG，升高了ST段高度，并增加了QT和QRS间期。它降低了心肌损伤标志物的水平，如肌酸激酶同工酶-MB和乳酸脱氢酶。DOX可升高血清SGOT和NO水平。其注射显著诱导心肌组织中的脂质过氧化反应，并降低心肌组织中先天性抗氧化剂如超氧化物歧化酶、过氧化氢酶和还原型谷胱甘肽的活性。DOX治疗升高了TNF-水平，并引起心肌组织学改变，如中性粒细胞浸润、肌坏死和水肿。用DS（2、10和50 mg/kg p.o. 7天）预防了ECG变化，最小化了氧化应激，并使DOX诱导的心脏毒性的生化指标正常化。DS还保护大鼠心脏免受DOX诱导的组织学改变。最近，DS被报道发挥癌细胞的化疗增敏作用。我们使用MCF 7细胞系的体外研究显示，DS逆转了DOX诱导的NF-B和Nrf 2表达抑制。这些关于DS对DOX诱导的心脏毒性的保护活性的研究结果证明了其作为癌症化疗辅助治疗的效用的详细研究。
In the present study, the preventive effects of orally administered disulfiram (DS) against the doxorubicin (DOX)-induced cardiotoxicity were investigated in rats. DS was orally administered for 7days at doses of 2, 10, and 50mg/kg/day. DOX (30mg/kg) was intraperitoneally administered on the 5th day of the initiation of DS treatment. Within 48h of injection, DOX treatment significantly altered ECG, elevated the ST height, and increased the QT and QRS intervals. It reduced the cardiac levels of injury markers like creatine kinase isoenzyme-MB and lactate dehydrogenase. DOX elevated the serum levels of SGOT and nitric oxide. Its injection significantly induced lipid peroxidation in the cardiac tissue and reduced the activities of innate antioxidants like super oxide dismutase, catalase, and reduced glutathione in the cardiac tissue. DOX treatment raised the TNF- level and caused histological alterations in the myocardium like neutrophil infiltrations, myonecrosis, and edema. Pre-treatment of rats with DS (2, 10, and 50mg/kg p. o. for 7days) prevented the ECG changes, minimized oxidative stress, and normalized the biochemical indicators of the DOX-induced cardiotoxicity. DS also protected rat heart from DOX-induced histological alterations. Recently, DS is reported to exert chemosensitization of cancer cells. Our in vitro investigation using MCF7 cell line revealed that DS reverses the DOX-induced suppression of NF-B and Nrf2 expression. These findings about the protective activity of DS against the DOX-induced cardiotoxicity warrant a detailed investigation on its utility as an adjunct therapy to cancer chemotherapy.