期刊
ACTA BIOMATERIALIA
卷 152, 期 -, 页码 380-392出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2022.08.024
关键词
Salinomycin; Combined chemotherapy; Wnt; j3-catenin; EMT; Tumor stemness
资金
- National Natural Science Foundation of China [51973136]
- Sichuan University Innovation Spark Project [2018SCUH0089]
A promising combined chemotherapeutic strategy using a targeted co-delivery nanosystem has been developed to overcome abnormal progression in drug-resistant tumor cells and cancer stem cells. The strategy effectively inhibits the Wnt/β-catenin signaling pathway and EMT process, leading to a reduction in tumor growth and metastasis risk.
The abnormal activation of the Wnt/ j3-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/ j3-catenin signaling pathway-related genes ( j3-catenin, LRP6, LEF1 , and TCF12 ) and target genes ( Cyclin D1, Cmyc , and Fibronectin ) as well as CSC stemness-related genes ( Oct4, Nanog , and Hes1 ) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression ( E-cadherin and Vimentin ) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and j3-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma.
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