Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells
Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells
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DOI：
10.1097/00001813-200502000-00008
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发表时间：
2005-02-01
影响因子：
2.3
通讯作者：
DeAngelis, LM
中科院分区：
文献类型：
--
作者：
Gu, B;DeAngelis, LM
我们比较了生物还原性抗肿瘤药物丝裂霉素C（MMC）和链黑菌素（SN）的细胞毒性，或没有DT-黄递酶（DTD）诱导剂富马酸二甲酯（DMF）在四个人胶质母细胞瘤细胞系与传统的化疗药物，1，3-双（2-氯乙基）-1-亚硝基脲（BCNU）。我们还检查了其他四种类型的癌细胞，以与胶质母细胞瘤细胞进行比较。用磺酰罗丹明B（SR B）试验测定细胞毒性，并用50%抑制浓度（IC 50）表示。用比色法测定细胞内DTD、细胞色素B（5）还原酶和谷胱甘肽-S-转移酶（GST）的活性。在胶质母细胞瘤细胞系中，BCNU的IC 50在28-300 μ M的范围内。胶质母细胞瘤细胞对MMC或SN的敏感性高于BCNU。DMF预处理可显著增加MMC和SN对胶质母细胞瘤细胞系和NCl-H1299肺癌细胞系的细胞毒作用，但对BCNU的细胞毒作用无影响。DMF显著增加了四种胶质母细胞瘤细胞系中三种的DTD和细胞色素B（5）还原酶活性，并降低了GST。在所有胶质母细胞瘤细胞系中，添加DTD抑制剂双香豆素可显著抑制MMC和SN的细胞毒性，并逆转DMF与MMC或SN组合时观察到的细胞毒性增加。将DTD和细胞色素B（5）还原酶诱导剂与生物还原剂联合使用可能是胶质母细胞瘤的一种潜在治疗策略。(C)2005年利平科特威廉姆斯威尔金斯。
We compared the cytotoxicity of the bioreductive antitumor agents mitomycin C (MMC) and streptonigrin (SN) with or without the DT-diaphorase (DTD) inducer dimethyl fumarate (DMF) in four human glioblastoma cell lines with the conventional chemotherapeutic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We also examined four other types of cancer cells to compare with glioblastoma cells. Cytotoxicity was measured with the sulforhodamine B (SRB) assay and was represented by 50% inhibition concentration (IC50). Enzymatic activities of DTD, cytochrome b(5) reductase and glutathione-S-transferase (GST) in cells were measured spectrophotometrically. IC50 for BCNU was in a range of 28-300 muM in the glioblastoma cell lines. Glioblastoma cells were more sensitive to MMC or SN than to BCNU. Pretreatment with DMF significantly increased cytotoxicity of MMC and SN in glioblastoma cell lines and the NCl-H1299 lung cancer cell line, but had no effect on BCNU cytotoxicity. DMF significantly increased DTD and cytochrome b(5) reductase activity, and decreased GST in three of four glioblastoma cell lines. Addition of the DTD inhibitor, dicumarol, significantly inhibited cytotoxicity of MMC and SN, and reversed the increased cytotoxicity seen when DMF was combined with either MMC or SN in all glioblastoma cell lines. Combining inducers of DTD and cytochrome b(5) reductase with bioreductive agents may be a potential therapeutic strategy for glioblastoma. (C) 2005 Lippincott Williams Wilkins.