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

Sunitinib, a multi-targeted tyrosine kinase inhibitor, has been widely used in the therapy of advanced renal cell cancer and imatinib-resistant gastrointestinal stromal tumors. However, little benefits could be obtained from sunitinib for patients with other types of solid tumors including colorectal cancer (CRC). Ethaselen (BBSKE), a specific thioredoxin reductase 1 inhibitor, has shown convincing anticancer effects both in vivo and in vitro. In this study, we explored the combinatory effect of sunitinib and BBSKE in human CRC cell lines LoVo, HT-29 and RKO. Cotreatment of BBSKE and sunitinib with the ratio of 2:1 for 24h displayed synergistic effect against CRC cells proliferation. Apoptosis analysis also revealed that combination treatment of BBSKE and sunitinib (2:1) for 24h induced higher apoptosis rate than either single treatment. The synergistic effect against LoVo cells proliferation may be explained by sharp reduction of Bcl-2/Bax protein expression ratio, decrease of pro-Caspase-3 protein expression along with significantly augmented Caspase-3 enzymatic activity, and release of cytochrome C from mitochondria to cytoplasm in the combination treatment group. The significant inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation might also account for the synergism in cotreatment group. In short, sunitinib plus BBSKE is perhaps a promising strategy for colorectal cancer therapy.

Topics: Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Synergism; Humans; Indoles; Inhibitory Concentration 50; Mitochondria; Organoselenium Compounds; Phosphorylation; Pyrroles; Sunitinib; Thioredoxin-Disulfide Reductase; Thioredoxins; Vascular Endothelial Growth Factor Receptor-2

Thioredoxin reductase (TrxR) is a ubiquitous intracellular redox enzyme that regulates tumor growth and proliferation in various cancer cells. Ethaselen (1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane), a novel anticancer agent, is designed to target mammalian TrxR1 with the aims of cancer growth inhibition and TrxR inactivation. In this study, we demonstrated that ethaselen significantly inhibits cell growth in the poorly differentiated colorectal RKO cell line, and simultaneously downregulates mammalian TrxR1 mRNA transcript levels, protein expression and enzyme activity, which differs from its actions in moderately differentiated colorectal LoVo cells. Ethaselen's significant abatement of the Wnt/beta-catenin cell differentiation-related signaling pathway was also observed in RKO cells; this apparently leads to its strong inhibitory effect on cell growth and TrxR1 activity in this cell line. These results suggest that ethaselen has a novel mechanism affecting cell growth in the poorly differentiated RKO colorectal cell line.

Topics: Antineoplastic Agents; beta Catenin; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Down-Regulation; Humans; Microarray Analysis; Organoselenium Compounds; Polymerase Chain Reaction; Protein Synthesis Inhibitors; RNA, Messenger; Signal Transduction; Thioredoxin Reductase 1; Wnt Proteins