Genistein Enhances the Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Inhibits Nuclear Factor Kappa B in Nonsmall Cell Lung Cancer Cell Lines (Retracted article. See vol. 122, pg. 3248, 2016)
Genistein Enhances the Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Inhibits Nuclear Factor Kappa B in Nonsmall Cell Lung Cancer Cell Lines (Retracted article. See vol. 122, pg. 3248, 2016)
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DOI：
10.1002/cncr.24250
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发表时间：
2009-05-15
期刊：
影响因子：
6.2
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Gadgeel, Shirish M.;Ali, Shadan;Sarkar, Fazlul H.
背景：表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)在复发性非小细胞肺癌(NSCLC)患者中显示出一定的临床益处。Akt的下调似乎与EGFR-TKI的抗肿瘤活性有关。AKT激活核因子-kappaB，核因子-kappaB转录对细胞存活、侵袭和转移至关重要的基因。作者推测，金雀异黄素通过抑制核因子-kappaB，可增强NSCLC中EGFR-TKI的活性。方法：选择3种不同EGFR突变状态和对EGFR-TKI敏感性不同的非小细胞肺癌细胞株：H3255(L858R)、H16SO(del E746-A750)和H1781(野生型EGFR)。用厄洛替尼、吉非替尼、金雀异黄素或每种EGFR-TKI与金雀异黄素的组合处理细胞。检测EGFR、PAKT、环氧合酶-2(COX-2)、E-钙粘素、前列腺素E-2(PGE(2))和核因子-kappaB的表达水平。结果：两种EGFR-TKI均表现出生长抑制和细胞凋亡，但H1650和H1781的敏感性较弱。金雀异黄素在所有细胞系中都显示出一定的抗肿瘤活性，但当与EGFR-TKI结合时，每一种细胞系的生长抑制和细胞凋亡都增强了。在H3255中，两种药物组合对核因子-KB的下调作用明显高于单独使用任何一种药物。此外，联合用药降低了EGFR、PAKT、COX-2和PGE2的表达，这与核因子-KB的失活一致。结论：金雀异黄素增强了EGFR-TKI在3种不同的NSCLC细胞系中的抗肿瘤作用。这种增强的活性部分是因为当EGFR-TKI与金雀异黄素结合时，核因子-kappa B的DNA结合活性更大地降低。癌症杂志2009；115：2165-76。(C)2009年美国癌症协会。
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown modest clinical benefit in patients with relapsed nonsmall cell lung cancer (NSCLC). Down-regulation of Akt appears to correlate with the antitumor activity of EGFR-TKIs. Akt activates nuclear factor kappa B (NF-kappa B), which transcribes genes important for cell survival, invasion, and metastasis. The authors hypothesized that genistein, through the inhibition of NF-kappa B, could enhance the activity of EGFR-TKIs in NSCLCs. METHODS: Three NSCLC cell lines with various EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H16SO (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, genistein, or the combination of each of the EGFR-TKIs with genistein. Cell survival and apoptosis were assessed, and expression levels of EGFR, pAkt, cyclooxygenase-2 (COX-2), E-cadherin, prostaglandin E-2 (PGE(2)), and NF-kappa B were measured, RESULTS: Both EGFR-TKIs demonstrated growth inhibition and apoptosis in each of the cell lines, but H1650 and H1781 were much less sensitive. Genistein demonstrated some antitumor activity in all cell lines, but enhanced growth inhibition and apoptosis when combined with the EGFR-TKIs in each of the cell lines. Both combinations down-regulated NF-KB significantly more than either agent alone in H3255. In addition, the combinations reduced the expression of EGFR, pAkt, COX-2, and PGE2, consistent with inactivation of NF-KB. CONCLUSIONS: The authors concluded that genistein enhances the antitumor effects of EGFR-TKIs in 3 separate NSCLC cell lines. This enhanced activity is in part because of greater reduction in the DNA-binding activity of NF-kappa B when EGFR-TKIs were combined with genistein. Cancer 2009;115:2165-76. (C) 2009 American Cancer Society.