Modulation of cisplatin cytotoxicity by sulphasalazine.
Modulation of cisplatin cytotoxicity by sulphasalazine.
复制标题
通过磺胺嗪调节顺铂细胞毒性。
DOI：
10.1038/bjc.1994.278
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发表时间：
1994-08
影响因子：
8.8
通讯作者：
Awasthi, Y C
中科院分区：
文献类型：
--
作者：
Awasthi, S;Sharma, R;Singhal, S S;Herzog, N K;Chaubey, M;Awasthi, Y C
顺铂[顺-二胺氯铂（II）]的疗效观察恶性细胞对其细胞毒性作用的获得性或新生耐药性阻碍了DDP。我们以前报道过顺铂耐药与几种人小细胞肺癌细胞系的谷胱甘肽s转移酶（GST）活性相似。在目前描述的研究中，我们使用磺胺嘧啶（一种GSTs抑制剂）来评估GSTs在两种人小细胞肺癌细胞系NCI H-69和H-2496中介导顺铂耐药的相对作用。H-69细胞株GST活性高于H-2496细胞株（分别为317 +/- 7 μ和9 +/- 1 μ mg-1蛋白），对顺铂的耐药程度也更高（IC50分别为25.0 +/- 3.9 μ和4.5 +/- 1.0 μ m）。纯化GST的Western blot和Northern blot分析显示，两种细胞系中仅表达pi类GST。在Ki值相似的情况下（H-69和H-2496细胞系分别为6.5和7.9微米），磺胺嘧啶以竞争的方式抑制纯化的GSTs （H-69和H-2496细胞系的IC50分别为10微米和12微米）。细胞毒性研究显示，磺胺嘧啶增加顺铂对两种细胞系的细胞毒性。等线图分析显示，磺胺嘧啶协同增强顺铂对两种细胞系的细胞毒性，H-69细胞的协同作用幅度明显高于H-2496细胞。我们的研究表明，临床可达到的磺胺嘧啶浓度可能有助于调节GST-pi含量增加的恶性肿瘤的顺铂耐药性。
The efficacy of cisplatin [cis-diamminedichloroplatinum (II); DDP] is hampered by acquired or de novo resistance of malignant cells to its cytotoxic effects. We have previously reported that cisplatin resistance parallels glutathione S-transferase (GST) activity in several human small-cell lung cancer cell lines. In the presently described studies, we used sulphasalazine, an inhibitor of GSTs, to evaluate the relative role of GSTs in mediating cisplatin resistance in two human small-cell lung cancer cell lines, NCI H-69 and H-2496. The H-69 cell line, which contained relatively higher GST activity than the H-2496 cell line (317 +/- 7 vs 9 +/- 1 mU mg-1 protein respectively), also displayed a greater degree of cisplatin resistance (IC50 values of 25.0 +/- 3.9 vs 4.5 +/- 1.0 microM respectively). Western blot and Northern blot analyses of purified GSTs revealed the expression of only the pi-class GST in both cell lines. Sulphasalazine inhibited the purified GSTs (IC50 of 10 microM for H-69 and 12 microM for H-2496) from both lines in a competitive manner with similar Ki values (6.5 and 7.9 microM for the H-69 and H-2496 cell lines respectively). Cytotoxicity studies revealed that sulphasalazine increased the cytotoxicity of cisplatin towards both cell lines. Isobologram analysis showed that sulphasalazine synergistically enhanced the cytotoxicity of cisplatin towards both cell lines, the magnitude of synergy being remarkably higher in H-69 cells than in H-2496 cells. Our studies indicate that clinically achievable concentrations of sulphasalazine may be useful in modulating cisplatin resistance in malignancies with increased GST-pi content.