The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation.
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.
Welsh
Sarah J
SJ
Arizona Cancer Center, Tucson, Arizona 85724, USA. swelsh@azcc.arizona.edu
Williams
Ryan R
RR
Birmingham
Anne
A
Newman
David J
DJ
Kirkpatrick
D Lynn
DL
Powis
Garth
G
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D004220:Disulfides; C497442:HIF1A protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D008565:Membrane Proteins; D014157:Transcription Factors; C491200:Txndc2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide; D008156:Luciferases; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C479485:pleurotin