Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells
Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells
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DOI：
10.1007/s00280-004-0959-y
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发表时间：
2004
影响因子：
3
通讯作者：
O. Kishida;Y. Miyazaki;Y. Murayama;M. Ogasa;T. Miyazaki;Takahiro Yamamoto;K. Watabe;S. Tsutsui;T. Kiyohara;I. Shimomura;Y. Shinomura
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文献类型：
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作者：
O. Kishida;Y. Miyazaki;Y. Murayama;M. Ogasa;T. Miyazaki;Takahiro Yamamoto;K. Watabe;S. Tsutsui;T. Kiyohara;I. Shimomura;Y. Shinomura
表皮生长因子受体（EGFR）及其配体参与肿瘤的生长、转移、血管生成和化疗耐药性。本文报道的研究结果表明，SN 38（CPT-11的活性代谢产物）在5 min内诱导EGFR的酪氨酸磷酸化，随后诱导AGS胃癌细胞中肝素结合EGF样生长因子、双调蛋白、转化生长因子-α和白细胞介素-8（IL-8）的转录物和/或蛋白质。SN 38还激活核因子-κB和激活蛋白-1，这两者对于IL-8基因的转录都是关键的。然而，通过EGFR-TKI（酪氨酸激酶抑制剂）吉非替尼（“易瑞沙”，ZD 1839）阻断EGFR活化，消除了所有上述反应。SN 38触发的机制包括活性氧（ROS）的产生和蛋白激酶C（PKC）的激活，随后是金属蛋白酶激活和EGFR配体的连续胞外域脱落。这些研究结果表明，EGF信号被CPT-11增强，并指出CPT-11与吉非替尼联合治疗某些胃癌的潜在益处。
The epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. The findings reported here demonstrate that SN38 (the active metabolite of CPT-11) induces the tyrosine phosphorylation of EGFR within 5 min, followed by the induction of transcripts and/or proteins of the heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-α, and interlukin-8 (IL-8) in AGS gastric cancer cells. SN38 also activates nuclear factor-κB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (“Iressa”, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.