The objective of this study was to determine whether paclitaxel and a strong antioxidant, pyrrolidinedithiocarbamate (PDTC), can affect the activation of nuclear factor-kappa B (NF-kappaB) in SKOV-3 human ovarian cancer cell line and the effect of these two agents on the growth and apoptosis of the cancer cells. The cells were treated with various concentrations of paclitaxel and/or PDTC at various time intervals. Following treatments, cell growth and apoptosis were determined by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphonyl)-2H-tetrazolium (WST-8) (WST) assay and flow cytometry, respectively. Western blot assay was used to determine the nuclear p65 protein and cytoplasmic IkappaB-alpha protein. High doses of PDTC significantly inhibited the growth of SKOV-3 cells and caused apoptosis. Paclitaxel and lower doses of PDTC combined demonstrated additive inhibition of cell growth and increased levels of apoptosis. Treatment of paclitaxel alone showed increased nuclear p65 protein and decreased cytoplasmic IkappaB-alpha protein expression, while pretreatment of PDTC reversed this function. PDTC blocks the paclitaxel-induced activation of NF-kappaB leading to increased chemosensitivity to paclitaxel and enhanced apoptosis. Combining antioxidants and paclitaxel has significant potential to overcome the risk of paclitaxel resistance.

译文

这项研究的目的是确定紫杉醇和强抗氧化剂吡咯烷二硫代氨基甲酸酯 (PDTC) 是否会影响SKOV-3人卵巢癌细胞系中核因子-κ B (NF-κ B) 的活化以及这两种药物对癌细胞生长和凋亡的影响。在不同的时间间隔用各种浓度的紫杉醇和/或PDTC处理细胞。处理后,通过2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二硫酰基)-2h-四唑 (WST-8) (WST) 测定和流式细胞仪测定细胞生长和凋亡。Western blot测定法用于测定核p65蛋白和细胞质IkappaB-α 蛋白。高剂量的PDTC显著抑制SKOV-3细胞的生长并引起细胞凋亡。紫杉醇和较低剂量的PDTC组合显示出对细胞生长的加性抑制和凋亡水平的增加。单独治疗紫杉醇显示核p65蛋白增加,胞质IkappaB-α 蛋白表达降低,而PDTC的预处理逆转了这一功能。PDTC阻断紫杉醇诱导的NF-κ b激活,从而增加对紫杉醇的化学敏感性并增强细胞凋亡。结合抗氧化剂和紫杉醇具有克服紫杉醇耐药性风险的巨大潜力。

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