Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells.

Abstract

New effective treatment for human non-small cell lung cancer (NSCLC) is needed. The thioredoxin (Trx) system composes of thioredoxin reductase (TrxR), Trx and NADPH. In this study, we combined an organic selenium compound--TrxR inhibitor ethaselen (BBSKE) with low dosage sodium selenite to inhibit proliferation and induce death of NSCLC cells, and identified underlying mechanisms. Synergistic anti-proliferation effect of BBSKE and selenite was found in human NSCLC cell lines, A549, NCI-H1299 and NCI-1266. A significant increase of apoptosis, necrosis and autophagy were observed in the group of BBSKE plus selenite in A549 cells. The autophagy induced by BBSKE and selenite inhibited apoptosis and necrosis. In addition, BBSKE plus selenite induced G2/M arrest, which was verified by the alteration of gene and protein expression of cell cycle regulatory complexes. The intracellular enzyme activity of TrxR was remarkably decreased by cotreatment of BBSKE and selenite. Besides, the mRNA and protein level of TrxR1 and Trx1 were significantly inhibited by cotreatment of BBSKE and selenite. HEK 293 cells overexpressing TrxR1 were more sensitive to BBSKE plus selenite. The nuclear translocation of Trx1 and Ref-1, as well as expression of Ref-1 and AP-1 were inhibited by combination treatment. In short, BBSKE synergizes selenite in inhibiting proliferation and inducing death of NSCLC cells; BBSKE combined with selenite may be a treatment strategy for NSCLC.

• Authors: Xiaoqing Zheng, Wei Xu, Ruoxuan Sun, Hanwei Yin, Chaoran Dong, Huihui Zeng
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 275 Pg. 74-85 (Sep 25 2017) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 28757135 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• (1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane
• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• MAP1LC3B protein, human
• Microtubule-Associated Proteins
• Organoselenium Compounds
• P62 protein, human
• RNA-Binding Proteins
• Transcription Factor AP-1
• Thioredoxins
• Thioredoxin-Disulfide Reductase
• Sodium Selenite

Topics

• A549 Cells
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacology)
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• HEK293 Cells
• Humans
• Lung Neoplasms (metabolism, pathology)
• Microtubule-Associated Proteins (metabolism)
• Organoselenium Compounds (chemistry, pharmacology)
• RNA-Binding Proteins (metabolism)
• Sodium Selenite (chemistry, pharmacology)
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors, metabolism)
• Thioredoxins (genetics, metabolism)
• Transcription Factor AP-1 (genetics, metabolism)