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

The expression and activity of thioredoxin reductase (TrxR) are significantly higher in tumor tissues than in normal tissues, but the correlation of plasma TrxR activity to tumor growth has seldom been reported. This study was to evaluate the correlation of plasma TrxR activity to the growth of hepatocellular carcinoma (HCC) H22 cell xenografts in mice.. H22 cells were injected subcutaneously into Kunming mice to establish HCC model. The mice were divided into control group, mice group, low dose (36 mg/kg), moderate dose (72 mg/kg) and high dose (216 mg/kg) ethaselen groups. The mice in control group and model group were given 0.5% sodium carboxymethyl cellulose (CMC-Na). Blood samples were drawn before tumor cell inoculation, when tumor volume reached 100 mm3, and at Days 1, 4 and 10 of treatment. TrxR activity in plasma and tumor tissues was detected by dithio-bis-nitrobenzoic acid (DTNB) method.. The inhibition rates of tumor growth were 59.5% in low dose ethaselen group, 74.3% in moderate dose ethaselen group, and 74.9% in high dose ethaselen group. Plasma TrxR activity was stable in control mice, and was correlated positively to tumor volume in tumor-bearing mice. At the end of treatment, the inhibition rates of TrxR activity in plasma and tumor were 59.2% and 15.3% in low dose ethaselen group, 68.4% and 25.8% in moderate dose ethaselen group, 68.9% and 29.8% in high dose ethaselen group.. Plasma TrxR activity is correlated positively to tumor growth. Ethaselen can inhibit TrxR activity corresponding to tumor growth inhibition.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Male; Mice; Neoplasm Transplantation; Organoselenium Compounds; Thioredoxin-Disulfide Reductase; Tumor Burden