Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride
Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride
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DOI：
10.1254/jphs.08219fp
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
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作者：
Akagi, Takanori;Fukagawa, Tatsuo;Ohdo, Shigehiro
在临床实践中，糖皮质激素经常被用来调节化疗药物的疗效和毒性。然而，糖皮质激素如何调节化疗药物的药理作用仍有待阐明。在这项研究中，我们建立了糖皮质激素受体(GR)缺陷的大鼠-1细胞，以研究GR在调节细胞对盐酸伊立替康(CPT-11)敏感性中的作用。地塞米松(DEX)处理野生型大鼠1细胞可显著增强CPT-11的细胞毒作用，而对CPT-11对GR缺陷细胞的细胞毒作用影响不大。DEX和CPT-11联合作用后野生型细胞的拓扑异构酶-I活性明显低于单独用CPT-11处理的细胞。Dex处理还增强了CPT-11对野生型细胞磷脂酰肌醇3-激酶-Akt信号通路的抑制作用，同时促进了caspase-3的活性。地塞米松对CPT-11诱导的细胞毒作用的调节作用在GR缺陷细胞中未观察到。我们的研究结果揭示了GCs增强CPT-11化疗效果的潜在机制，并提示GCs与GCs联合治疗可能会减少CPT-11的剂量，从而在不降低抗肿瘤活性的情况下减轻不良反应。
In clinical practice, glucocorticoids are often used with the aim of modulating the efficacy and toxicity of chemotherapeutic agents. However, how glucocorticoids modulate the pharmacological action of chemotherapeutic agents remains to be clarified. In this study, we generated glucocorticoid receptor (GR)-deficient rat-1 cells to investigate the role of GR in the regulation of cellular sensitivity to irinotecan hydrochloride (CPT-11). Treatment of wild-type rat-1 cells with dexamethasone (DEX) significantly enhanced the cytotoxic effect of CPT-11, whereas the treatment had little effect on the cytotoxicity of CPT-11 in GR-deficient cells. Topoisomerase-I activity in wild-type cells after concomitant treatment with DEX and CPT-11 was significantly lower than that after treatment with CPT-11 alone. DEX treatment also enhanced the inhibitory action of CPT-11 on the phosphatidylinositol 3-kinase-Akt signaling pathway in wild-type cells, accompanied by facilitating caspase-3 activity. These modulatory effects of DEX on the CPT-11-induced cytotoxicity were not observed in GR-deficient cells. Our present findings reveal the underlying mechanism by which GCs enhance the chemotherapeutic effect of CPT-11 and indicate the possibility that the dosage of CPT-11 could be reduced by the combination treatment with GCs, which may attenuate the adverse effect without decreasing anti-tumor activity.