The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in tumor growth by increasing resistance to apoptosis and the production of angiogenic factors such as vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer comprised of oxygen-regulated HIF-1alpha and constitutively expressed HIF-1beta subunits. The redox protein thioredoxin-1 (Trx-1), which is found at high levels in many human cancers, increases both aerobic and hypoxia-induced HIF-1alpha protein in cells leading to increased expression of HIF-regulated genes. We have investigated whether two cancer drugs that inhibit Trx-1 signaling, PX-12 (1-methylpropyl 2-imidazolyl disulfide) and pleurotin, decrease HIF-1alpha protein levels and the expression of downstream target genes. Treatment of MCF-7 human breast cancer and HT-29 human colon carcinoma cells with PX-12 and pleurotin prevented the hypoxia (1% oxygen)-induced increase in HIF-1alpha protein. HIF-1-trans-activating activity, VEGF formation, and inducible nitric oxide synthase were also decreased by treatment with PX-12 and pleurotin under hypoxic conditions. PX-12 and pleurotin also decreased HIF-1alpha protein levels and HIF-1 trans-activation in RCC4 renal cell carcinoma cells that constitutively overexpress HIF-1alpha protein because of loss of the pVHL gene, indicating that HIF-1alpha is inhibited independently of the pVHL pathway. HIF-1alpha and VEGF protein levels in MCF-7 tumor xenografts in vivo were decreased by PX-12 treatment of mice. The results suggest that inhibition of HIF-1alpha by Trx-1 inhibitors may contribute to the growth inhibitory and antitumor activity of these agents.

• Authors: Sarah J Welsh, Ryan R Williams, Anne Birmingham, David J Newman, D Lynn Kirkpatrick, Garth Powis
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 2 Issue 3 Pg. 235-43 (Mar 2003) ISSN: 1535-7163 [Print] United States
• PMID: 12657718 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Disulfides
• HIF1A protein, human
• Heterocyclic Compounds, 4 or More Rings
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles
• Membrane Proteins
• Transcription Factors
• Txndc2 protein, mouse
• Vascular Endothelial Growth Factor A
• Thioredoxins
• 1-methylpropyl-2-imidazolyl disulfide
• Luciferases
• NOS2 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• pleurotin

Topics

• Animals
• Blotting, Western
• Breast Neoplasms (metabolism)
• Cell Division (drug effects)
• Colonic Neoplasms (metabolism)
• Disulfides (pharmacology)
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles (pharmacology)
• Immunoenzyme Techniques
• Kidney Neoplasms (metabolism)
• Luciferases (metabolism)
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, SCID
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Thioredoxins (antagonists & inhibitors, metabolism)
• Transcription Factors (antagonists & inhibitors)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)