Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

Novel thioredoxin inhibitors paradoxically increase hypoxia-inducible factor-alpha expression but decrease functional

Dylan T Jones1, Christopher W Pugh, Simon Wigfield

  • 1Cancer Research UK Growth Factor Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 27, 2006
PubMed
Summary

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Generating exosome subtypes: diverse membrane origins and mergers.

Trends in cell biology·2026
Same author

SET1B Drives Sustained HIF activity and Disease Progression in Clear Cell Renal Cell Carcinoma.

Cancer research·2026
Same author

Editorial Expression of Concern: Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.

Nature medicine·2026
Same author

A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding.

Communications medicine·2025
Same author

Tumor-specific CD8 T cell characterization in HR<sup>+</sup> breast cancer reveals an impaired antitumoral response in patients with lymph node metastasis.

Cell reports. Medicine·2025
Same author

Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.

The EMBO journal·2025
This summary is machine-generated.

Novel anticancer drugs AJM290 and AW464 inhibit hypoxia-inducible factor-alpha (HIF-alpha) transcription activity and DNA binding. These drugs also prevent HIF-alpha degradation, offering a new therapeutic strategy for cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hypoxia-inducible factor-alpha (HIF-alpha) is a key transcription factor regulating cellular response to low oxygen.
  • Elevated HIF-alpha levels are observed in numerous cancers, making it a significant therapeutic target.
  • Thioredoxin-1 (Trx-1) is a redox protein that enhances both aerobic and hypoxia-induced HIF-alpha.

Purpose of the Study:

  • To investigate the efficacy of novel anticancer drugs AJM290 and AW464, which inhibit Trx-1, in modulating the HIF pathway.
  • To determine if these quinol-based drugs can inhibit HIF-alpha activity and its downstream effects in cancer cells.

Main Methods:

  • Treatment of various cancer cell lines with AJM290 and AW464.
  • Assessment of vascular endothelial growth factor (VEGF) levels under normoxic and hypoxic conditions.

Related Experiment Videos

  • Analysis of HIF-alpha expression, target gene regulation (carbonic anhydrase IX, VEGF, BNIP3), and transcriptional activity using reporter gene assays.
  • Investigation of the specific domain of HIF-1alpha affected by AJM290 through transfection studies.

    • Main Results:

    • AJM290 and AW464 inhibited hypoxia-induced VEGF increase at subtoxic concentrations.
    • The drugs decreased VEGF in pVHL mutant renal cell carcinoma cells with constitutive HIF-alpha overexpression.
    • Surprisingly, AJM290 and AW464 up-regulated HIF-alpha expression in breast cancer cell lines and pVHL mutant cells.
    • Inhibition of HIF-alpha target gene expression and HIF-alpha-dependent transcriptional activity and DNA binding was observed.
    • AJM290 was found to inhibit the transcriptional activity of both full-length HIF-1alpha and its COOH-terminal transactivation domain (CAD).

    Conclusions:

    • AJM290 and AW464 act as inhibitors of HIF-1alpha CAD transcriptional activity and DNA binding.
    • Unlike other Trx inhibitors, these drugs also inhibit the degradation of HIF-alpha.
    • These findings highlight a dual mechanism of action for AJM290 and AW464, targeting both HIF-alpha activity and stability for potential cancer therapy.