Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo.

Abstract

Ethaselen (1, 2-[bis (1, 2-Benzisoselenazolone-3 (2H) -ketone)] ethane, BBSKE), as a novel organoselenium compound targeting thioredoxin reductase (TrxR), has been reported to inhibit tumor growth and TrxR activity in several human tumor cell lines. It has now entered Phase I clinical trails. Here we report the effects of ethaselen and cisplatin (cis-diamminedichloroplatinum II, DDP) combination therapy (ethaselen 36 mg/kg, i.g., o.d. x 10 d and cisplatin 1 mg/kg, i.p., single at day 0) on human A549-grafted nude mouse model (female, BALB/c nude mouse, n = 5, treatment after tumor volume reached 100 mm(3)). Compared to single drug administration (either ethaselen: 36 mg/kg, i.g., o.d. x 10 d or cisplatin: 1.0 mg/kg, i.p., single at day 0), the combination therapy showed significantly reduced tumor size (presumably due to a synergistic effect) and no obvious toxic damage (both in terms of body weight maintenance and liver/kidney damage). These results will be significant in the development of novel anti-tumoral therapeutic strategies directed to non-small cell lung cancer (NSCLC).

• Authors: Qiang Tan, Jing Li, Han-wei Yin, Li-hui Wang, Wan-chen Tang, Fang Zhao, Xin-min Liu, Hui-hui Zeng
• Journal: Investigational new drugs (Invest New Drugs) Vol. 28 Issue 3 Pg. 205-15 (Jun 2010) ISSN: 1573-0646 [Electronic] United States
• PMID: 19271154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Organoselenium Compounds
• ethaselen-1
• Glutathione Peroxidase
• Thioredoxin-Disulfide Reductase
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Body Weight (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Cisplatin (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Inhibitors (therapeutic use)
• Female
• Glutathione Peroxidase (metabolism)
• Humans
• Kidney (anatomy & histology, drug effects, metabolism)
• Kidney Function Tests
• Lipid Peroxidation (drug effects)
• Liver (anatomy & histology, drug effects, metabolism)
• Liver Function Tests
• Mice
• Mice, Nude
• Organoselenium Compounds (administration & dosage, pharmacology)
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors)
• Xenograft Model Antitumor Assays