Cancer. 2016, 122(20):3248.

Genistein Enhances the Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Inhibits Nuclear Factor Kappa B in No nsmall Cell Lung Cancer Cell Lines

Shirish M. Gadgeel, Shadan Ali, Philip A. Philip, et al

Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; et al

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-kappaB), which transcribes genes important for cell survival, invasion, and metastasis. The authors hypothesized that genistein, through the inhibition of NF-kappaB, 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), H1650 (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-kappaB 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-kappaB significantly more than either agent alone in H3255. In addition, the combinations reduced the expression of EGFR, pAkt, COX-2, and PGE(2,) consistent with inactivation of NF-kappaB.

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-kappaB when EGFR-TKIs were combined with genistein.

美国《癌症》2016, 122(20):3248.

在非小细胞肺癌细胞中，染料木黄酮增强表皮生长因子受体酪氨酸激酶抑制剂的作用并抑制核因子κB

Shirish M. Gadgeel, Shadan Ali, Philip A. Philip, et al

美国密歇根州底特律韦恩州立大学Karmanos癌症研究所血液学/肿瘤学系; et al

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）患者中显示出适度的临床益处。 Akt的下调似乎与EGFR-TKI的抗肿瘤活性相关。 Akt激活核因子κB（NF-kappaB），其转录对于细胞存活，侵袭和转移重要的基因。作者假设染料木素通过抑制NF-kappaB可以增强EGFR-TKIs在NSCLC中的活性。

方法：

选择具有各种EGFR突变状态和对EGFR-TKI的敏感性的三种NSCLC细胞系：H3255（L858R），H1650（del E746-A750）和H1781（野生型EGFR）。细胞用厄洛替尼，吉非替尼，染料木素或每种EGFR-TKI与染料木素的组合处理。评估细胞存活和凋亡，并测量EGFR，pAkt，环加氧酶-2（COX-2），E-钙粘蛋白，前列腺素E（2）（PGE（2））和NF-κB的表达水平。

结果：

两种EGFR-TKIs在每个细胞系中证明了生长抑制和细胞凋亡，但是H1650和H1781的敏感性低得多。染料木素在所有细胞系中显示出一些抗肿瘤活性，但当与每种细胞系中的EGFR-TKIs组合时增强生长抑制和细胞凋亡。两种组合在H3255中显着多于单独的任一试剂下调NF-κB。此外，该组合降低了EGFR，pAkt，COX-2和PGE（2）的表达，与NF-κB的失活一致。

结论：

作者得出结论，染料木素增强EGFR-TKIs在3个单独的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与染料木黄酮组合时，NF-κB的DNA结合活性的更大降低。