Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells
Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells
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DOI：
10.1016/s0014-2999(01)00858-5
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发表时间：
2001-03-23
影响因子：
5
通讯作者：
Peters, GJ
中科院分区：
文献类型：
--
作者：
Bergman, AM;Pinedo, HM;Peters, GJ
吉西他滨被脱氧胞苷激酶和胸苷激酶2磷酸化，并在S期掺入DNA。调节细胞增殖和基因表达的类固醇皮质醇和地塞米松通过膜外排泵P-糖蛋白和多药耐药相关蛋白（MRP）泵出细胞，这些泵被维拉帕米阻断。在亲本非小细胞肺癌（NSCLC）细胞（SW 1573）中，5 μ M皮质醇和100 nM地塞米松降低了对吉西他滨的敏感性。然而，浴皮质醇和地塞米松仅降低MRP（2 R120）和P-糖蛋白（2 R160）过表达变异体对维拉帕米的敏感性。皮质醇降低SW 1573细胞的脱氧胞苷激酶活性，皮质醇与维拉帕米合用降低2 R120和2 R160细胞的脱氧胞苷激酶活性。地塞米松和维拉帕米降低2 R160的脱氧胞苷激酶活性。皮质醇降低2 R120和2 R160细胞胸苷激酶2活性。地塞米松降低SW 1573、2 R120和2 R160细胞胸苷激酶2活性。总之，由于地塞米松经常用于治疗溶瘤治疗的副作用，因此类固醇对吉西他滨的敏感性降低可能具有临床意义。(C)2001 Elsevier Science B. V.保留所有权利。
Gemcitabine is phosphorylated by deoxycytidine kinase and thymidine kinase 2 and during S-phase incorporated into DNA. The steroids cortisol and dexamethasone, which regulate cell proliferation and gene expression, are pumped out of the cell by the membrane efflux pumps P-glycoprotein and multidrug resistance-associated protein (MRP), which are blocked by verapamil. In parental non-small cell lung cancer (NSCLC) cells (SW1573), 5 muM cortisol and 100 nM dexamethasone decreased sensitivity to gemcitabine. However, bath cortisol and dexamethasone only decreased sensitivity with verapamil in MRP (2R120) and P-glycoprotein (2R160) overexpressing variants. Cortisol decreased deoxycytidine kinase activity in SW1573 cells and cortisol with verapamil in 2R120 and 2R160 cells. Dexamethasone with verapamil decreased deoxycytidine kinase activity in 2R160. Cortisol decreased thymidine kinase 2 activity in 2R120 and 2R160 cells. Dexamethasone decreased thymidine kinase 2 activity in SW1573, 2R120 and 2R160 cells. In conclusion, since dexamethasone is frequently used to treat side effects of oncolytic therapy, a decrease of sensitivity to gemcitabine by steroids might be clinically relevant. (C) 2001 Elsevier Science B.V. All rights reserved.