Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells.
Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells.
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DOI：
10.1186/bcr1028
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发表时间：
2005
影响因子：
7.4
通讯作者：
Pollak, M
中科院分区：
文献类型：
--
作者：
Camirand, A;Zakikhani, M;Young, F;Pollak, M
吉非替尼（Iressa, ZD 1839, AstraZeneca）阻断表皮生长因子受体（EGFR）的酪氨酸激酶活性，抑制包括乳腺癌在内的几种人类癌细胞类型的增殖。吉非替尼单药治疗的II期临床试验显示，非小细胞肺癌患者的客观缓解率为9%至19%，乳腺癌患者的客观缓解率低于10%，而III期临床试验结果表明，吉非替尼联合化疗比单独化疗没有益处。为了提高吉非替尼的抗肿瘤活性，我们研究了阻断胰岛素样生长因子1受体（IGF-1R）信号传导的作用，IGF-1R是一种酪氨酸激酶，在大多数人类原发性乳腺癌中与EGFR共表达，在恶性肿瘤中起着至关重要的作用。AG1024（一种IGF-1R抑制剂）与吉非替尼一起用于治疗MDA468、MDA231、SK-BR-3和MCF-7乳腺癌系，它们表达相似水平的IGF-1R，但表达不同水平的EGFR。用AG1024和吉非替尼单独或联合处理的细胞进行增殖试验、细胞凋亡诱导研究和Western blot分析。吉非替尼和AG1024单独使用时，在所有细胞系中均能降低增殖，联合使用时显示出对细胞生长抑制的加和增效作用。用膜联蛋白v -碘化丙啶染色的细胞和caspase-3活化染色的细胞的流式细胞术测量表明，与单独使用吉非替尼相比，在吉非替尼中加入igf - 1r靶向策略导致更高水平的凋亡。吉非替尼降低或完全抑制p42/p44 Erk激酶磷酸化，这取决于细胞系，而Akt磷酸化被两种药物联合降低。SK-BR-3细胞中IGF-1R的过表达足以引起吉非替尼耐药性的显著增强。这些结果表明，IGF-1R信号传导降低了吉非替尼在几种乳腺癌细胞系中的抗增殖作用，并且在吉非替尼治疗中加入抗IGF-1R策略可能比单一药物治疗更有效。
Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas. AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination. Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance. These results indicate that IGF-1R signaling reduces the antiproliferative effects of gefitinib in several breast cancer cell lines, and that the addition of an anti-IGF-1R strategy to gefitinib treatment may be more effective than a single-agent approach.
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影响因子：
45.3
作者：
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通讯作者：
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