Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan.
Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
Molecules. 2020 Feb 19;25(4):941. doi: 10.3390/molecules25040941.
Epidermal growth factor receptor (EGFR) is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC), which is the major type of lung cancer. The EGFR tyrosine kinase inhibitors (TKIs) are the approved treatment for patients harboring activating mutations in the EGFR kinase. However, most of the patients treated with EGFR-TKIs developed resistance. Therefore, the development of compounds exhibiting unique antitumor activities might help to improve the management of NSCLC patients. The total flavonoids from Sieb. et Zucc. have been shown to contain antitumor activity. Here, we have isolated a novel flavonoid hydroxygenkwanin (HGK) that displays selective cytotoxic effects on all of the NSCLC cells tested. In this study, we employed NSCLC cells harboring EGFR mutations and xenograft mouse model to examine the antitumor activity of HGK on TKI-resistant NSCLC cells. The results showed that HGK suppressed cancer cell viability both in vitro and in vivo. Whole-transcriptome analysis suggests that EGFR is a potential upstream regulator that is involved in the gene expression changes affected by HGK. In support of this analysis, we presented evidence that HGK reduced the level of EGFR and inhibited several EGFR-downstream signalings. These results suggest that the antitumor activity of HGK against TKI-resistant NSCLC cells acts by enhancing the degradation of EGFR.
表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）中经常过表达和突变，这是非小细胞肺癌的主要类型。EGFR 酪氨酸激酶抑制剂（TKI）是针对 EGFR 激酶中存在激活突变的患者的批准治疗方法。然而，大多数接受 EGFR-TKI 治疗的患者产生了耐药性。因此，开发具有独特抗肿瘤活性的化合物可能有助于改善 NSCLC 患者的管理。山金车属植物的总黄酮已被证明具有抗肿瘤活性。在这里，我们分离出一种新型的黄酮类化合物羟考酮（HGK），它对所有测试的 NSCLC 细胞均显示出选择性细胞毒性作用。在这项研究中，我们使用携带 EGFR 突变的 NSCLC 细胞和异种移植小鼠模型来检查 HGK 对 TKI 耐药 NSCLC 细胞的抗肿瘤活性。结果表明，HGK 抑制了体外和体内的癌细胞活力。全转录组分析表明，EGFR 是一个潜在的上游调节剂，参与了 HGK 影响的基因表达变化。为了支持这一分析，我们提供了证据表明 HGK 降低了 EGFR 的水平并抑制了几个 EGFR 下游信号通路。这些结果表明，HGK 对 TKI 耐药 NSCLC 细胞的抗肿瘤活性通过增强 EGFR 的降解而起作用。
