Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.
Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.
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DOI：
10.3892/ijo.32.3.683
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发表时间：
2008-03
影响因子：
5.2
通讯作者：
T. Sumikawa;Y. Shigeoka;T. Igishi;H. Suyama;A. Yamasaki;Kiyoshi Hashimoto;S. Matsumoto;K. Takeda;Y. Ueda;E. Shimizu
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文献类型：
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作者：
T. Sumikawa;Y. Shigeoka;T. Igishi;H. Suyama;A. Yamasaki;Kiyoshi Hashimoto;S. Matsumoto;K. Takeda;Y. Ueda;E. Shimizu
曲妥珠单抗与紫杉醇（PTX）的联合治疗是治疗 HER2 阳性乳腺癌的重要选择。地塞米松 (Dex) 术前用药通常用于 PTX 治疗。在 BT-474 细胞中评估 Dex、PTX 和曲妥珠单抗之间的相互作用。 Dex 干扰曲妥珠单抗诱导的细胞生长抑制，但对 PTX 诱导的细胞毒性没有明显影响。曲妥珠单抗去磷酸化视网膜母细胞瘤蛋白 (pRB)。 Dex 恢复了曲妥珠单抗诱导的 pRB 去磷酸化，并释放了曲妥珠单抗诱导的 G1 期阻滞。曲妥珠单抗抑制 AKT 活性而不影响 ERK 活性。磷脂酰肌醇 3-激酶/AKT 途径的特异性抑制剂 LY294002 可抑制细胞生长以及 AKT 和 pRB 磷酸化。 Dex 恢复了曲妥珠单抗诱导的 AKT 抑制，而不影响 ERK 活性。结论是，Dex 至少部分通过恢复 BT-474 乳腺癌细胞中曲妥珠单抗诱导的 AKT 抑制和随后的 pRB 去磷酸化来干扰曲妥珠单抗诱导的细胞生长抑制。这些观察结果支持开发无需糖皮质激素术前用药的新化疗方案。
The combination of trastuzumab with paclitaxel (PTX) is an important option for the treatment of HER2-positive breast cancer. Dexamethasone (Dex) premedication is routinely used in the treatment with PTX. The interactions among Dex, PTX and trastuzumab were evaluated in BT-474 cells. Dex interfered with trastuzumab-induced cell growth inhibition without clear effects on PTX-induced cytotoxicity. Trastuzumab dephosphorylated retinoblastoma protein (pRB). Dex restored this trastuzumab-induced dephosphorylation of pRB and released trastuzumab-induced G1 arrest. Trastuzumab suppressed AKT activity without affecting ERK activity. A specific inhibitor for the phosphatidylinositol 3-kinase/AKT pathway, LY294002, inhibited cell growth and AKT and pRB phosphorylation. Dex restored the trastuzumab-induced suppression of AKT without affecting ERK activity. It was concluded that Dex interferes with trastuzumab-induced cell growth inhibition, at least partially, through the restoration of trastuzumab-induced AKT suppression and subsequent pRB dephosphorylation in BT-474 breast cancer cells. These observations support the development of new chemotherapeutic regimens without glucocorticoid premedication.