Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha.

Abstract

We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1alpha (HIF-1alpha) within the tumor. We now report that PX-478 inhibits HIF-1alpha protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1alpha inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1alpha mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5' untranslated region of HIF-1alpha. Moreover, to a lesser extent, PX-478 also inhibits HIF-1alpha deubiquitination resulting in increased levels of polyubiquitinated HIF-1alpha. The inhibitory effect of PX-478 on HIF-1alpha levels is primarily due to its inhibition of translation because HIF-1alpha translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1alpha at multiple levels that together or individually may contribute to its antitumor activity against HIF-1alpha-expressing tumors.

• Authors: Mei Y Koh, Taly Spivak-Kroizman, Sara Venturini, Sarah Welsh, Ryan R Williams, D Lynn Kirkpatrick, Garth Powis
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 1 Pg. 90-100 (Jan 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18202012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
• Antineoplastic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mustard Compounds
• Phenylpropionates
• Tumor Suppressor Protein p53

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Molecular Structure
• Mustard Compounds (chemistry, pharmacology)
• Phenylpropionates (chemistry, pharmacology)
• Protein Biosynthesis (drug effects, genetics)
• Sensitivity and Specificity
• Time Factors
• Transcription, Genetic (drug effects, genetics)
• Transcriptional Activation (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitination