Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells.
Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells.
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DOI：
10.3892/ijo.30.1.187
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发表时间：
2007
影响因子：
5.2
通讯作者：
M. Morita;H. Suyama;T. Igishi;Y. Shigeoka;M. Kodani;Kiyoshi Hashimoto;K. Takeda;T. Sumikawa;E. Shimizu
中科院分区：
文献类型：
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作者：
M. Morita;H. Suyama;T. Igishi;Y. Shigeoka;M. Kodani;Kiyoshi Hashimoto;K. Takeda;T. Sumikawa;E. Shimizu
非小细胞肺癌的治疗方法有哪些？超敏反应是紫杉醇临床应用中的主要不良反应之一。糖皮质激素用于预防这些不良事件。本研究旨在阐明糖皮质激素对紫杉醇诱导的癌细胞毒性的影响。用10 μ M地塞米松预处理抑制ERK激活和随后的视网膜母细胞瘤蛋白（pRB）磷酸化，并降低A549细胞对紫杉醇的敏感性。然后，我们使用ERK（PD98059）和AKT（LY294002）抑制剂。PD98059和LY294002有效抑制A549细胞中pRB磷酸化。地塞米松（10 μ M）抑制ERK活性以及PD98059，虽然它不影响AKT活性。此外，紫杉醇与PD98059或LY294002的组合具有类似的拮抗作用。我们在这项研究中的观察提出了地塞米松预处理通过ERK抑制和pRB去磷酸化拮抗紫杉醇诱导的细胞毒性的可能性。这些观察结果支持开发新一代紫杉烷为基础的化疗无糖皮质激素前驱用药。
Paclitaxel is used frequently for the treatment of patients with non-small cell lung cancer. Hypersensitivity reactions remain one of the major adverse events in the clinical use of paclitaxel. Glucocorticoids are used to prevent these adverse events. This study was carried out in order to clarify the effect of glucocorticoids on paclitaxel-induced cytotoxity of cancer cells. Pretreatment with 10 microM of dexamethasone inhibited ERK activation and subsequent retinoblastoma protein (pRB) phosphorylation, and reduced sensitivity to paclitaxel in A549 cells. Then, we utilized ERK (PD98059) and AKT (LY294002) inhibitors. PD98059 and LY294002 effectively suppressed pRB phosphorylation in A549 cells. Dexamethasone (10 microM) suppressed ERK activity as well as PD98059, although it did not affect AKT activity. Furthermore, the combinations of paclitaxel with PD98059 or LY294002 were similarly antagonistic. Our observation in this study raised the possibility that dexamethasone pretreatment antagonizes paclitaxel-induced cytotoxicity through ERK suppression and pRB dephosphorylation. These observations support the development of new generation taxane-based chemotherapy without glucocorticoid premedication.