Roller A, Bähr O R, Streffer J, Winter S, Heneka M, Deininger M, Meyermann R, Naumann U, Gulbins E, Weller M
Department of Neurology, University of Tübingen, Tübingen, Germany.
Biochem Biophys Res Commun. 1999 Jun 16;259(3):600-5. doi: 10.1006/bbrc.1999.0825.
Here, we report that nonsteroidal anti-inflammatory drugs (NSAID) enhance the cytotoxic effects of doxorubicin and vincristine in T98G human malignant glioma cells. The cytotoxicity of BCNU, cisplatin, VM26, camptothecin, and cytarabine is unaffected by NSAID. No free radical formation is induced by doxorubicin or vincristine in the absence or presence of NSAID. Doxorubicin and vincristine cytotoxicity in the absence or presence of NSAID are unaffected by free radical scavengers. Functional inhibitors of phospholipase A2 (PLA2), such as dexamethasone and quinacrine, do not mimick the effects of NSAID. T98G cells, but not LN-18, LN-229, LN-308, or A172 glioma cells, express cyclooxygenase (COX-1) and NSAID do not modulate drug cytotoxicity in the other cell lines, except T98G. Thus, augmentation of doxorubicin and vincristine cytotoxicity by NSAID correlates with COX-1 expression. However, ectopic expression of COX-1 in LN-229 cells does not induce the phenotype of T98G cells, indicating that COX-1 inhibition does not mediate the effects of NSAID on drug cytotoxicity. In contrast, a multidrug resistance (MDR) phenotype due to expression of the multidrug resistance-associated protein (MRP) is most prominent in T98G cells and is amenable to modulation by indomethacin, suggesting that inhibition of MRP is at least in partly responsible for the potentiation of doxorubicin and vincristine cytotoxicity by NSAID.
在此，我们报告非甾体抗炎药（NSAID）可增强阿霉素和长春新碱对T98G人恶性胶质瘤细胞的细胞毒性作用。卡莫司汀、顺铂、替尼泊苷、喜树碱和阿糖胞苷的细胞毒性不受NSAID影响。在有无NSAID存在的情况下，阿霉素或长春新碱均不诱导自由基形成。有无NSAID存在时，阿霉素和长春新碱的细胞毒性均不受自由基清除剂影响。磷脂酶A2（PLA2）的功能抑制剂，如地塞米松和奎纳克林，不能模拟NSAID的作用。T98G细胞表达环氧化酶（COX-1），而LN-18、LN-229、LN-308或A172胶质瘤细胞则不表达，除T98G外，NSAID对其他细胞系的药物细胞毒性无调节作用。因此，NSAID增强阿霉素和长春新碱的细胞毒性与COX-1表达相关。然而，COX-1在LN-229细胞中的异位表达并未诱导出T98G细胞的表型，这表明COX-1抑制并不介导NSAID对药物细胞毒性的作用。相反，多药耐药相关蛋白（MRP）表达所致的多药耐药（MDR）表型在T98G细胞中最为显著，且可被吲哚美辛调节，这表明MRP抑制至少部分负责NSAID增强阿霉素和长春新碱的细胞毒性。
