Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment

• Published in: Journal of Zhejiang University. B. Science Vol. 21; no. 3; pp. 218 - 233
• Main Authors: Liu, Xuan, Zhou, Xue-qing, Shang, Xu-wei, Wang, Li, Li, Yi, Yuan, Hong, Hu, Fu-qiang
• Format: Journal Article
• Language: English
• Published: Hangzhou Zhejiang University Press 01.03.2020; Springer Nature B.V
• Subjects: Amines - chemistry; Antineoplastic Agents - adverse effects; Biomedical and Life Sciences; Biomedicine; Botulinum toxin; Breast cancer; Breast Neoplasms - pathology; Chemotherapy; Chitosan; Chitosan - chemistry; Cytoskeleton; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug delivery; Drug Delivery Systems; Epithelial-Mesenchymal Transition - drug effects; Female; Gene transfer; Glutathione; Humans; In vivo methods and tests; Invasiveness; MCF-7 Cells; Mesenchyme; Metastases; Metastasis; Neoplasm Metastasis - prevention & control; Oxidation-Reduction; Proteins; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - physiology; Rac1 protein; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Small Interfering - administration & dosage; Sensitivity enhancement; siRNA; Stearylamine; Substrates; Toxins; Tumor cells; Tumors; 皮质间质样转化 (EMT); Ras-related C3 botulinum toxin substrate 1 (RAC1); 肿瘤转移; 小干扰; 壳聚糖胶束; Small interfering RNA (siRNA); RNA (siRNA); Doxorubicin; R945; Epithelial-mesenchymal transition (EMT); 阿霉素 (DOX); RAC1; Chitosan micelles; Tumor metastasis; Doxorubicin; Tumor metastasis; Ras-related C3 botulinum toxin substrate 1 (RAC1); Epithelial-mesenchymal transition (EMT); Chitosan micelles; Small interfering RNA (siRNA)
• ISSN: 1673-1581; 1862-1783
• DOI: 10.1631/jzus.B1900468

Metastasis is one of the main reasons causing death in cancer patients. It was reported that chemotherapy might induce metastasis. In order to uncover the mechanism of chemotherapy-induced metastasis and find solutions to inhibit treatment-induced metastasis, the relationship between epithelial-mesenchymal transition (EMT) and doxorubicin (DOX) treatment was investigated and a redox-sensitive small interfering RNA (siRNA) delivery system was designed. DOX-related reactive oxygen species (ROS) were found to be responsible for the invasiveness of tumor cells in vitro, causing enhanced EMT and cytoskeleton reconstruction regulated by Ras-related C3 botulinum toxin substrate 1 (RAC1). In order to decrease RAC1, a redox-sensitive glycolipid drug delivery system (chitosan-ss-stearylamine conjugate (CSO-ss-SA)) was designed to carry siRNA, forming a gene delivery system (CSO-ss-SA/siRNA) down-regulating RAC1. CSO-ss-SA/siRNA exhibited an enhanced redox sensitivity compared to nonresponsive complexes in 10 mmol/L glutathione (GSH) and showed a significant safety. CSO-ss-SA/siRNA could effectively transmit siRNA into tumor cells, reducing the expression of RAC1 protein by 38.2% and decreasing the number of tumor-induced invasion cells by 42.5%. When combined with DOX, CSO-ss-SA/siRNA remarkably inhibited the chemotherapy-induced EMT in vivo and enhanced therapeutic efficiency. The present study indicates that RAC1 protein is a key regulator of chemotherapy-induced EMT and CSO-ss-SA/siRNA silencing RAC1 could efficiently decrease the tumor metastasis risk after chemotherapy.