Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
Toxicol In Vitro. 2014 Mar;28(2):248-57. doi: 10.1016/j.tiv.2013.11.001. Epub 2013 Nov 12.
Cisplatin, a cancer chemotherapy drug, is nephrotoxic. The aim of this study was to investigate whether resveratrol (RES) reduced cisplatin cytotoxicity and oxidative stress. Rat renal cortical slices were pre-incubated 30min with 0 (VEH, ethanol) or 30μg/ml RES followed by 60, 90 or 120min co-incubation with 0, 75, or 150μg/ml cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90min by cisplatin. Cisplatin increased (p<0.05) LDH leakage at 120min which was protected by RES. Cisplatin induced oxidative stress prior to LDH leakage as cisplatin depressed glutathione peroxidase and superoxide dismutase (SOD) activity, increased lipid peroxidation, protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins within 60min. RES failed to reverse glutathione (GSH) depression by cisplatin. In order to eliminated an extracellular interaction between RES and cisplatin, additional studies (RINSE studies) allowed a 30min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120min cisplatin incubation. RES in the RINSE studies prevented LDH leakage by cisplatin indicating that RES protection was not via a physical interaction with cisplatin in the media. These findings indicate that RES diminished cisplatin in vitro renal toxicity and prevented the development of oxidative stress.
顺铂是一种癌症化疗药物，具有肾毒性。本研究旨在探讨白藜芦醇（RES）是否降低顺铂的细胞毒性和氧化应激。将大鼠肾皮质切片用 0（VEH，乙醇）或 30μg/ml RES 预孵育 30min，然后与 0、75 或 150μg/ml 顺铂共同孵育 60、90 或 120min。60 和 90min 时，顺铂对乳酸脱氢酶（LDH）漏出无影响。120min 时，顺铂增加了 LDH 漏出，而 RES 则对此具有保护作用。在 LDH 漏出之前，顺铂诱导了氧化应激，因为顺铂抑制了谷胱甘肽过氧化物酶和超氧化物歧化酶（SOD）的活性，增加了脂质过氧化、蛋白质羰基和 4-羟壬烯醛（4-HNE）加合物蛋白在 60min 内的产生。RES 未能逆转顺铂引起的 GSH 减少。为了消除 RES 和顺铂之间的细胞外相互作用，进行了额外的研究（冲洗研究），使 RES 在切片中摄取 30min，然后将切片转移到缺乏 RES 的缓冲液中，再进行 120min 的顺铂孵育。RES 在冲洗研究中防止了顺铂引起的 LDH 漏出，表明 RES 的保护作用不是通过与培养基中的顺铂发生物理相互作用来实现的。这些发现表明，RES 减轻了顺铂的体外肾毒性，并防止了氧化应激的发展。
