Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress

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 30 min with 0 (VEH, ethanol) or 30 μg/ml RES followed by 60, 90 or 120 min co-incubation with 0, 75, or 150 μg/ml cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90 min by cisplatin. Cisplatin increased (p < 0.05) LDH leakage at 120 min 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 60 min. 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 30 min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120 min 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.     

Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is partially involved in the pathogenesis of cispaltin-induced nephrotoxicity.     

切除修复交叉互补基因1调控卵巢癌耐药株A2780/顺铂迁移及侵袭的作用

目的探讨切除修复交叉互补基因1(ERCC1)调节卵巢癌耐药株A2780/顺铂(DDP)细胞迁移及侵袭能力的作用及其机制。方法根据细胞对顺铂的耐药性,分为普通组A2780、顺铂耐药组A2780/DDP。细胞计数试剂盒(CCK-8)检测A2780、A2780/DDP细胞活性及顺铂耐药性。Transwell细胞迁移、侵袭实验检测A2780、A2780/DDP细胞的迁移和侵袭能力。蛋白质印迹法(Western blot)检测A2780、A2780/DDP细胞中ERCC1、上皮表型E-钙黏蛋白(E-cadherin)及间质表型波形蛋白(Vimentin)的表达。小干扰RNA(siRNA)-ERCC1转染A2780/DDP中ERCC1表达后,Transwell细胞迁移、侵袭实验检测细胞迁移和侵袭能力的改变,Western blot检测细胞中ERCC1、E-cadherin及Vimentin表达的改变。两组间比较采用Student’s-t检验。结果A2780/DDP的半抑制浓度(IC50)值为17.66 mg/L,A2780的IC50值为2.236 mg/L,A2780/DDP较A2780的IC50提高了7.898倍。A2780/DDP细胞的迁移和侵袭能力明显高于非耐药株,且A2780/DDP中ERCC1和间质表型Vimentin的表达明显高于非耐药株A2780,而上皮表型E-cadhetin表达明显低于A2780。干扰A2780/DDP中ERCC1表达后,细胞的迁移和侵袭能力明显低于对照组,且细胞中ERCC1和间质表型Vimentin的表达低于对照组,而上皮表型E-cadhetin表达高于对照组。结果差异均有统计学意义。结论A2780/DDP中高表达的ERCC1通过促进细胞发生上皮-间充质转化增强细胞的迁移及侵袭的能力。     

Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905)

IntroductionIn malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential.MethodsS0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme.ResultsA total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7).ConclusionsCediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.     

Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer

The treatment of advanced non-small cell lung cancer (NSCLC) may be changing, but the cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced NSCLC. In this respect, changes in practice to various aspects of cisplatin use, such as administration schedules and the choice of methods and frequency of monitoring for toxicities, have contributed to an incremental improvement in patient management and experience. Chemoresistance, however, limits the clinical utility of this drug in patients with advanced NSCLC. Better understanding of the molecular mechanisms of cisplatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required. In addition to maximising potential benefits from advances in molecular biology and associated therapeutics, modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences.     

诱导化疗在局部中晚期口腔鳞癌序贯治疗中功能保留作用的研究

目的 探讨诱导化疗(DBF和TPF方案)在口腔癌序贯治疗中的作用,观察诱导化疗后患者口腔功能的差异.方法 回顾性分析2009年1月至2011年1月我科口腔鳞癌中晚期病例,共47例(UICC分期Ⅲ~Ⅳ期)口腔鳞癌患者,其中男35例,女12例.中位年龄55岁(29~72岁).试验组病例用TPF方案或DBF方案诱导化疗两个疗程,化疗结束后2~3周行影像学检查,根据影像学结果评价是否可行手术治疗.对照组病例直接行手术治疗,术后评估患者外观、口腔功能、发音、社会功能等.结果 47例患者中15例患者诱导化疗后行手术治疗.32例患者直接行手术治疗.两组患者相比较,诱导化疗组原发灶肿瘤平均值大小>直接手术组,两组原发灶肿瘤大小有统计学差异(P<0.05).两组患者口腔功能评估,外观、口腔功能、发音、社会功能无明显差别.结论 诱导化疗后肿瘤原发灶缩小,使患者获得手术机会,缩小手术范围,可使术后口腔功能与直接手术组功能相似.