Conjugates Derived from Lapatinib Derivatives with Cancer Cell Stemness Inhibitors Effectively Reversed Drug Resistance in Triple-Negative Breast Cancer.
Yuanjiang WangZhaodan LvFeihong ChenXing WangShaohua GouPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- signaling pathway
- induced apoptosis
- cell cycle arrest
- pi k akt
- drug resistant
- epithelial mesenchymal transition
- stem cells
- small cell lung cancer
- cell proliferation
- cell death
- cancer stem cells
- positive breast cancer
- oxidative stress
- multidrug resistant
- metastatic breast cancer
- endoplasmic reticulum stress
- epidermal growth factor receptor
- risk assessment
- cell migration
- tyrosine kinase
- breast cancer cells
- climate change
- high glucose
- endothelial cells
- cystic fibrosis
- pseudomonas aeruginosa
- case report
- smoking cessation
- human health
- drug delivery