(1-2-bis(1-2-benzisoselenazolone-3(2h)-ketone))ethane and Breast-Neoplasms

Treating cancer metastasis is of vital importance to prolong patients' survival. Thioredoxin reductase (TrxR) is overexpressed in many cancer types and has been recognized as an anti-cancer target. The organoselenium compound ethaselen (BBSKE) has been proved to be a TrxR inhibitor and inhibit various types of tumor growth. However, whether BBSKE could inhibit tumor metastasis remains unclear. In this study, we aim to explore the antimetastatic effect of BBSKE and underlying mechanisms. BBSKE was found to dose-dependently suppress migration and invasion of MCF-7 and LoVo cells in vitro. The underlying mechanisms may include inhibition of TrxR activity, elevation of reactive oxygen species (ROS), decrease of EGFR activation and HER2 expression. Besides, the epithelial to mesenchymal transition process and expression of CD44, MMP-9, VEGFR2 and PD-L1 were also abrogated. Decreased migration and invasion, lower expression levels of EGFR, HER2, N-cadherin, CD44, MMP-9, VEGFR2 and PD-L1 were also observed in TrxR1-knockdown MCF-7 and LoVo cells. In the mouse breast cancer 4T1 model, BBSKE not only inhibited progression of primary tumor, but also suppressed formation of metastatic lung nodules and liver micro-metastases, indicating that BBSKE could effectively abolish tumor metastasis. In conclusion, our findings show that BBSKE is able to inhibit migration and invasion of cancer cells in vitro and in vivo, and may be used to prevent and treat metastasis.

Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Liver Neoplasms; Lung Neoplasms; Matrix Metalloproteinase 9; MCF-7 Cells; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Organoselenium Compounds; Oxidative Stress; Reactive Oxygen Species; Receptor, ErbB-2; Signal Transduction; Thioredoxin Reductase 1; Tumor Burden

Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme. On the other hand, overexpression of TrxR1 is closely correlated with the initiation of various tumors including breast cancer, though the detailed mechanism remains unclear. Here we investigated the role of TrxR1 in dysplastic transformation of human breast epithelial cell line MCF-10A induced by chronic oxidative stress. Not surprisingly, sustained exposure to H

Topics: Adult; Animals; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cadherins; Cell Line; Cell Movement; Cell Survival; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Fibrocystic Breast Disease; Humans; Hydrogen Peroxide; Keratin-7; MCF-7 Cells; Mice; Mice, Nude; Microscopy, Confocal; Middle Aged; Models, Biological; Organoselenium Compounds; Oxidative Stress; Reactive Oxygen Species; Thioredoxin Reductase 1; Transplantation, Heterologous