Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride

DOI Web Site 被引用文献1件 参考文献42件
  • Akagi Takanori
    Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Fukagawa Tatsuo
    National Institute of Genetics and The Graduate University for Advanced Studies, Japan
  • Kage Yuki
    Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • To Hideto
    Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan
  • Matsunaga Naoya
    Department of Pharmaceutics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Koyanagi Satoru
    Department of Pharmaceutics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Uchida Akiko
    Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Fujii Asuka
    Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Iba Hideo
    Division of Host-Parasite Interaction, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Japan
  • Ikemura Toshimichi
    National Institute of Genetics and The Graduate University for Advanced Studies, Japan
  • Aramaki Hironori
    Department of Molecular Biology, Daiichi College of Pharmaceutical Sciences, Japan
  • Higuchi Shun
    Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan
  • Ohdo Shigehiro
    Department of Pharmaceutics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Japan

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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.<br> [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.08219FP]<br>

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