Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α
Open accessAbstract
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-1α (HIF-1α) within the tumor. We now report that PX-478 inhibits HIF-1α 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-1α inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1α mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5′ untranslated region of HIF-1α. Moreover, to a lesser extent, PX-478 also inhibits HIF-1α deubiquitination resulting in increased levels of polyubiquitinated HIF-1α. The inhibitory effect of PX-478 on HIF-1α levels is primarily due to its inhibition of translation because HIF-1α translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1α at multiple levels that together or individually may contribute to its antitumor activity against HIF-1α-expressing tumors. [Mol Cancer Ther 2008;7(1):90–100]
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PX-478 inhibits HIF-1α at multiple levels, primarily by translational inhibition and, to a lesser extent, by promoting protein degradation in an oxygen-, pVHL-, and p53-independent manner.
“PX-478 inhibits HIF-1α at multiple levels, primarily by translational inhibition and, to a lesser extent, by promoting protein degradation in an oxygen-, pVHL-, and p53-independent manner (Koh et al., 2008).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Koh et al., 2008
The Discussion reports that PX-478 inhibits HIF-1α at multiple levels, with reduced mRNA and translation playing major roles; its effect occurs in normoxia and hypoxia without requiring pVHL or p53. But the ‘PX-478 Modulates HIF-1α Ubiquitination’ section says that, although degradation initially increases, PX-478 does not change the overall rate of HIF-1α degradation. Thus, describing promotion of protein degradation as an established lesser mechanism overstates the finding. (LLM, conf=0.89)
Experimental — accuracy not yet measuredPX-478 antitumor activity appears mediated primarily by anti-angiogenic effects rather than cytotoxicity.
“Consequently, antitumor activity appears to be mediated primarily by anti-angiogenic effects rather than cytotoxicity [284].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [284]
The section “PX-478 Decreases Nuclear HIF-1α Protein and Inhibits HIF-1 Activity” says that inhibition of VEGF formation and angiogenesis mediates PX-478’s in vivo antitumor activity in part. It does not say these effects are the primary mechanism or establish that they outweigh cytotoxicity; its cytotoxicity comparison concerns hypoxic versus normoxic cultured cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPX-478 demonstrates effective passage across the blood-brain barrier and reduces HIF-1α levels through multiple mechanisms, including inhibition of HIF1A transcription, suppression of translation, and interference with HIF-1α deubiquitination.
“PX-478 demonstrates effective passage across the blood–brain barrier and reduces HIF-1α levels through multiple mechanisms, including inhibition of HIF1A transcription, suppression of translation, and interference with HIF-1α deubiquitination [284].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [284]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredPX-478 leaves HIF-1α protein stability largely unaltered, while inhibiting translational output through a nonspecific pathway that does not trigger the classical integrated stress response.
“Mechanistic interrogation indicates that PX-478 leaves HIF-1α protein stability largely unaltered, while inhibiting translational output through a nonspecific pathway that does not trigger the classical integrated stress response.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [284]
The ubiquitination section reports an initial increase in HIF-1α degradation but no change in its overall degradation rate. The translation results and Discussion report reduced HIF-1α synthesis and global translation under hypoxia, with no PX-478-induced change in eIF-2α phosphorylation. They do not establish a nonspecific pathway or rule out the integrated stress response as a whole; the Discussion instead describes HIF-1α as the major protein affected under hypoxia. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPX-478 effect preferentially impacts hypoxia-associated proteins including HIF-1α, leading to reduced nuclear localization and diminished transcription of angiogenic target genes.
“This effect preferentially impacts hypoxia-associated proteins, including HIF-1α, and leads to reduced nuclear localization and diminished transcription of angiogenic target genes.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [284]
The Discussion reports reduced HIF-1 activity and reduced hypoxia-mediated expression of VEGF, an angiogenic target. The section ‘PX-478 Decreases Nuclear HIF-1α Protein and Inhibits HIF-1 Activity’ reports lower nuclear HIF-1α levels, but explicitly says PX-478 does not affect its subcellular distribution or nuclear import. Thus, reduced nuclear localization is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
PX-478 suppresses constitutive and hypoxia-induced levels of HIF-1α in cancer cells.
“PX-478 (S-2-amino-3-[4V-N,N,-bis(2-chloroethyl) amino]-phenyl propionic acid N-oxide dihydrochloride) is a specific agent that suppresses constitutive and hypoxia-induced levels of HIF-1α in cancer cells [13, 14].”
From Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma (2015) · cites this paper as [13]
PX-478 lowers HIF-1α levels by affecting multiple levels: inhibition of deubiquitination, reduction of mRNA, and inhibition of translation.
“It was suggested that PX-478 lowers HIF-1α levels by affecting multiple levels in the HIF-1α pathway: (1) inhibition of HIF-1α deubiquitination via p53 and pVHL independent mechanism, resulting in increased levels of polyubiquitinated HIF-1α; (2) reduction of HIF-1α mRNA expression; and (3) inhibition of HIF-1α translation.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [87]
Pharmacologic depletion of HIF1α by PX478 and Digoxin produced similar results in T and NK cells.
“Likewise, pharmacologic depletion of HIF1α by small molecules PX478 and Digoxin41,42 also produced similar results in T and NK cells (Fig. 4g, h and Fig. S5f, g, h).”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 47 · Cited by 309
Research works printed but not linked: 2
- [26]26. Strayhorn WD, Wadzinski BE. A novel in vitro assay for deubiquiti- nation of InBa. Arch Biochem Biophys 2002;400:76 -84.
- [39]39. Rapisarda A, Zalek J, Hollingshead M, et al. Schedule-dependent inhibition of hypoxia-inducible factor-1a protein accumulation, angiogen- esis, and tumor growth by topotecan in U251HRE glioblastoma xeno- grafts. Cancer Res 2004;64:6845 -8.
- Authors
- Koh, M. Y., Spivak-Kroizman, T., Venturini, S., Welsh, S., Williams, R. R., Kirkpatrick, D. L., & Powis, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Arizona (US)
- 3ProlX Pharmaceuticals, Tucson, Arizona
- Venue
- Molecular Cancer Therapeutics
- Published
- 2008-01-01
- Volume
- 7
- Issue
- 1
- Pages
- 90-100
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2127096730
- Cited by
- 309
- References
- 47
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 23 · 2023: 25 · 2022: 27 · 2021: 20 · 2020: 22 · 2019: 16 · 2018: 12 · 2017: 16 · 2016: 13 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 14
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 90821, CA109552., R01CA077204, U54CA090821, CA077204, P01CA109552)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- PX-478, HIF-1α, HIF-1, anticancer activity, vascular endothelial growth factor, polyubiquitination, 5' untranslated region, p53-independent, tumor xenografts
- MeSH terms
- Antineoplastic Agents, Cell Nucleus, Humans, Mustard Compounds, Phenylpropionates, Sensitivity and Specificity, Time Factors, Transcription, Genetic, Protein Biosynthesis, Molecular Structure, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
