Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
J Physiol Pharmacol. 2017 Apr;68(2):295-308.
The anticancer drugs doxorubicin (DOX), paclitaxel (PTX) and docetaxel (DTX) have been proven to induce oxidative stress (OS)-dependent side-effects in non-targeted tissues. In normal conditions, the blood-brain barrier (BBB) prevents these drugs from penetrating into the brain. However, some studies have demonstrated that small amounts of DOX can penetrate the brain via an oxidatively impaired BBB and cause damage, which suggests that including antioxidants in chemotherapy could possibly protect the brain against the toxicity of anticancer drugs. We investigated whether DOX, DTX and PTX can induce oxidative damage in rat brains in vivo and whether inclusion of the nitroxyl antioxidant Pirolin (PL) to DOX/taxane chemotherapy can protect the brain from the OS toxicity of these drugs. Wistar rats received i.p. a single dose (10 mg/kg b.w.) of DOX, DTX, PTX or PL alone or a combination of a drug + PL. After four days, the rats were anesthetized, the brains were excised, homogenized and used for the measurements of lipid peroxidation (LPO), thiol groups, activities of antioxidant enzymes, DNA damage and tumor necrosis factor-α (TNF-α), neuronal nitric oxide synthase (nNOS) and poly (ADP-ribose) polymerase-1 (PARP-1) expression. The results were analyzed using the Kruskal-Wallis and Conover-Inman tests or ANOVA and the Tukey-Kramer test. Doxorubicin, PTX and DTX induced OS, DNA damage and changes in expression of TNF-α, nNOS and PARP-1 in the rat brain. Pirolin alone increased LPO, manganese superoxide dismutase (MnSOD) and catalase (CAT) activities and the expression of PARP-1 but decreased TNF-α expression. PL, in combination with anticancer drugs, partially protected the rat brain against the toxic effects of DOX and taxanes. The best protective effects of PL were obtained with PTX. Pirolin partially attenuated brain damage caused by DOX/taxanes, highlighting its potential application in protecting the brain against DOX-, DTX- and PTX-evoked OS.
阿霉素（DOX）、紫杉醇（PTX）和多西紫杉醇（DTX）等抗癌药物已被证明会在非靶向组织中引起氧化应激（OS）相关的副作用。在正常情况下，血脑屏障（BBB）可阻止这些药物穿透入脑。然而，一些研究表明，少量 DOX 可通过氧化损伤的 BBB 穿透入脑并造成损伤，这表明在化疗中加入抗氧化剂可能有助于保护大脑免受抗癌药物的毒性影响。我们研究了 DOX、DTX 和 PTX 是否可在体内诱导大鼠脑的氧化损伤，以及将抗氧化剂氮氧自由基 Pirolin（PL）加入 DOX/紫杉烷化疗中是否能保护大脑免受这些药物的 OS 毒性。Wistar 大鼠接受腹腔注射单剂量（10 mg/kg b.w.）的 DOX、DTX、PTX 或 PL 单独或药物+PL 联合。四天后，麻醉大鼠，取出大脑，匀浆后用于测量脂质过氧化（LPO）、巯基基团、抗氧化酶活性、DNA 损伤以及肿瘤坏死因子-α（TNF-α）、神经元型一氧化氮合酶（nNOS）和多聚（ADP-核糖）聚合酶-1（PARP-1）的表达。采用 Kruskal-Wallis 和 Conover-Inman 检验或 ANOVA 和 Tukey-Kramer 检验分析结果。DOX、PTX 和 DTX 可诱导 OS、DNA 损伤以及 TNF-α、nNOS 和 PARP-1 的表达改变。PL 单独使用可增加 LPO、锰超氧化物歧化酶（MnSOD）和过氧化氢酶（CAT）活性以及 PARP-1 的表达，但降低 TNF-α 的表达。PL 与抗癌药物联合使用可部分保护大鼠脑免受 DOX 和紫杉烷的毒性作用。PL 与 PTX 联合使用的保护效果最佳。PL 部分减轻了 DOX/紫杉烷引起的脑损伤，突出了其在保护大脑免受 DOX、DTX 和 PTX 诱导的 OS 中的潜在应用。
