拉帕蒂尼
三阴性乳腺癌
癌症研究
Wnt信号通路
化学
癌症干细胞
表皮生长因子受体抑制剂
癌细胞
转移
乳腺癌
蛋白激酶B
癌症
药理学
信号转导
生物
医学
内科学
生物化学
曲妥珠单抗
表皮生长因子受体
受体
作者
Yuanjiang Wang,Zhaodan Lv,Feihong Chen,Xing Wang,Shaohua Gou
标识
DOI:10.1021/acs.jmedchem.1c01013
摘要
Increasing evidence indicates that the cancer stem cell (CSC) subpopulation contributes to the therapeutic resistance and metastasis of tumors, leading to patient recurrence and death. Herein, we designed and synthesized several compounds by conjugating lapatinib derivatives with different CSC inhibitors to treat with lapatinib-induced MDA-MB-231 drug-resistant cells. In vitro biological studies indicated that 3a showed strong cytotoxicity and EGFR enzyme inhibitory activity and effectively reversed lapatinib-mediated resistance of MDA-MB-231 cells via inhibiting triple-negative breast cancer (TNBC) cell stemness and the AKT/ERK signaling pathway. In addition, 3a was capable of strongly suppressing the invasion and migration of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway and MMP-2 and MMP-9 protein expression. In vivo tumorigenicity tests showed that 3a could inhibit the occurrence of TNBC by inhibiting BCSCs, proving 3a is a potential EGFR and CSC dual inhibitor for TNBC treatment.
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