Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways
Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways
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白鲜宁是一种新型 c-Met 抑制剂，通过下调 PI3K/AKT/mTOR 和 MAPK 信号通路抑制肺癌细胞的增殖
DOI：
10.1016/j.bcp.2021.114864
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发表时间：
2022
影响因子：
5.8
通讯作者：
Xu Tian-Rui
中科院分区：
文献类型：
--
作者：
Yu Jiaojiao;Zhang Lijing;Peng Jun;Ward Richard;Hao Peiqi;Wang Jiwei;Zhang Na;Yang Yang;Guo Xiaoxi;Xiang Cheng;An Su;Xu Tian-Rui
白藓碱（Dic）是一种天然存在的小分子呋喃并喹啉生物碱，从Dictamnus dasycarpus Turcz.的根皮中分离得到，据报道显示出抗癌特性。然而，Dic的直接靶蛋白和抗癌机制知之甚少。目前研究发现，Dic在体内外均能抑制肺癌细胞的生长，并通过抑制受体酪氨酸激酶c-Met的磷酸化和激活，减弱PI 3 K/AKT/mTOR和丝裂原活化蛋白激酶（MAPK）信号通路的激活。此外，Dic与c-Met的结合通过使用细胞热位移试验（CETSA）和药物亲和力响应靶稳定性（DARTS）试验来证实。在所有检测的癌细胞系中，Dic抑制c-Met依赖性EBC-1细胞增殖的效力最大（IC 50 = 2.811 μM）。值得注意的是，Dic显示出协同提高表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）抗性肺癌细胞对吉非替尼和奥希替尼的化学敏感性。这些结果表明，Dic是一种c-Met抑制剂，可以作为一种潜在的治疗药物治疗肺癌，特别是对EGFR TKI耐药和c-Met依赖性肺癌。
Dictamnine (Dic), a naturally occurring small-molecule furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display anticancer properties. However, little is known about the direct target proteins and anticancer mechanisms of Dic. In the current study, Dic was found to suppress the growth of lung cancer cells in vitro and in vivo, and to attenuate the activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting the phosphorylation and activation of receptor tyrosine kinase c-Met. Moreover, the binding of Dic to c-Met was confirmed by using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Among all cancer cell lines tested, Dic inhibited the proliferation of c-Met-dependent EBC-1 cells with the greatest potency (IC50= 2.811 μM). Notably, Dic was shown to synergistically improve the chemo-sensitivity of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung cancer cells to gefitinib and osimertinib. These results suggest that Dic is a c-Met inhibitor that can serve as a potential therapeutic agent in the treatment of lung cancer, especially against EGFR TKI-resistant and c-Met-dependent lung cancer.