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Morphine Deteriorates Cisplatin-Induced Cardiotoxicity in Rats and Induces Dose-Dependent Cisplatin Chemoresistance in MCF-7 Human Breast Cancer Cells
Cardiovascular Toxicology ( IF 3.2 ) Pub Date : 2021-04-01 , DOI: 10.1007/s12012-021-09646-1
Azza A K El-Sheikh 1, 2 , Zenat Khired 3
Affiliation  

Morphine (MOR) is a strong analgesic that is often used in treatment of severe pains during cancer treatment, and thus might be concomitantly used with anticancer drugs as cisplatin (CP). The aim of the current study was to investigate the mechanisms by which MOR can affect CP-induced cardiotoxicity and to explore effects of MOR on the cytotoxic efficacy of CP. MOR (10 mg/kg/day i.p.) was administered to rats for 10 days, with or without 7.5 mg/kg CP single i.p. dose at day 5 of the experiment. In addition, MOR and/or CP were administered to MCF-7 cells to test their cytotoxicity. Compared to control, CP caused cardiotoxic effects manifested by significant increase in serum enzymatic markers; creatine kinase-MB and lactate dehydrogenase, with histopathological cardiac damage. In addition, CP caused cardiac oxidative stress, manifested by significant increased tissue lipid peroxidation product; malondialdehyde and nitric oxide, with significant decrease in tissue antioxidants as reduced glutathione, superoxide dismutase and catalase compared to control. Furthermore, CP significantly increased tissue proinflammatory cytokines; TNF-α and IL-6, as well as upregulated the apoptotic marker; caspase 3 compared to control. MOR/CP combination significantly deteriorated all tested parameters compared to CP alone. In MCF-7 breast cancer cells, administration of MOR in concentrations of 0.1, 1, 10 or 30 μM concomitantly with 1 or 10 μM CP caused dose-dependent reduction in CP-induced cytotoxicity in vitro. In conclusion, MOR administration might deteriorate CP-induced cardiotoxicity during cancer chemotherapy through oxidant, pro-inflammatory and apoptotic mechanisms, and might reduce CP chemotherapeutic efficacy.



中文翻译:

吗啡恶化顺铂诱导的大鼠心脏毒性并诱导 MCF-7 人乳腺癌细胞的剂量依赖性顺铂化学抗性

吗啡 (MOR) 是一种强镇痛剂,常用于治疗癌症治疗期间的剧烈疼痛,因此可能与顺铂 (CP) 等抗癌药物同时使用。本研究的目的是研究 MOR 影响 CP 诱导的心脏毒性的机制,并探讨 MOR 对 CP 的细胞毒功效的影响。MOR (10 mg/kg/day ip) 给予大鼠 10 天,在实验第 5 天有或没有 7.5 mg/kg CP 单次 ip 剂量。此外,将 MOR 和/或 CP 施用于 MCF-7 细胞以测试它们的细胞毒性。与对照相比,CP引起心脏毒性作用,表现为血清酶标志物显着增加;肌酸激酶-MB 和乳酸脱氢酶,伴有组织病理学心脏损伤。此外,CP引起心脏氧化应激,表现为组织脂质过氧化产物显着增加;丙二醛和一氧化氮,与对照相比,组织抗氧化剂如还原型谷胱甘肽、超氧化物歧化酶和过氧化氢酶显着减少。此外,CP 显着增加组织促炎细胞因子;TNF-α 和 IL-6,以及上调凋亡标志物;caspase 3 与对照相比。与单独的 CP 相比,MOR/CP 组合显着恶化了所有测试参数。在 MCF-7 乳腺癌细胞中,在 0.1、1、10 或 30 μM 浓度的 MOR 与 1 或 10 μM C​​P 的同时给药导致 CP 诱导的体外细胞毒性的剂量依赖性降低。总之,MOR 给药可能通过氧化、促炎和凋亡机制恶化癌症化疗期间 CP 诱导的心脏毒性,

更新日期:2021-04-02
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