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Cited by 40Immunotherapy and Immune ResponsesToxic Organic Pollutants ImpactImmunotoxicology and immune responses

SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for Immunomodulation

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Mezrich, Joshua D., Nguyen, Linh P., Kennedy, Greg, Nukaya, Manabu, Fechner, John H., Zhang, Xiaoji, Xing, Yongna, Bradfield, Christopher A.·2012·PLoS ONE
DOI 10.1371/journal.pone.0044547PMC PMC3435281
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Abstract

The experimental compound SU5416 went as far as Phase III clinical trials as an anticancer agent, putatively because of its activity as a VEGFR-2 inhibitor, but showed poor results. Here, we show that SU5416 is also an aryl hydrocarbon receptor (AHR) agonist with unique properties. Like TCDD, SU5416 favors induction of indoleamine 2,3 dioxygenase (IDO) in immunologically relevant populations such as dendritic cells in an AHR-dependent manner, leading to generation of regulatory T-cells in vitro. These characteristics lead us to suggest that SU5416 may be an ideal clinical agent for treatment of autoimmune diseases and prevention of transplant rejection, two areas where regulatory ligands of the AHR have shown promise. At the same time, AHR agonism might represent a poor characteristic for an anticancer drug, as regulatory T-cells can inhibit clearance of cancer cells, and activation of the AHR can lead to upregulation of xenobiotic metabolizing enzymes that might influence the half-lives of co-administered chemotherapeutic agents. Not only does SU5416 activate the human AHR with a potency approaching 2,3,7,8-tetrachlorodibenzo-p-dioxin, but it also activates polymorphic murine receptor isoforms (encoded by the Ahr(d) and Ahr(b1) alleles) with similar potency, a finding that has rarely been described and may have implications in identifying true endogenous ligands of this receptor.

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  • In hypomorphic mice treated with SU5416, about 59% displayed normal ductus venosus closure compared with about 4% of vehicle-treated controls.

    “Similarly, in hypomorphic mice treated with the AHR agonist SU5416, ~59% of mice displayed normal DV closure compared to ~4% of vehicle treated controls (Mezrich et al., 2012).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Mezrich et al., 2012

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Cited by

Sorted by citations

Authors
Mezrich, J. D., Nguyen, L. P., Kennedy, G., Nukaya, M., Fechner, J. H., Zhang, X., Xing, Y., & Bradfield, C. A.
Affiliations
  • University of Wisconsin–Madison (US)
  • Stanford Medicine (US)
Corresponding author
Mezrich, Joshua D.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-09-06
Volume
7
Issue
9
Pages
e44547
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0044547
PMC
PMC3435281
OpenAlex
W2140666029
Cited by
40
References
7
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 7 · 2019: 2 · 2018: 5 · 2017: 5 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 1
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • American Society of Nephrology
  • National Institutes of Health (UL1TR000427)
  • National Cancer Institute (P30CA014520)
  • National Institute of General Medical Sciences (R01GM096060)
  • National Institute of Environmental Health Sciences (K08ES017283, R37ES005703, R01ES005703)
  • National Center for Research Resources (UL1RR025011)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
SU5416, VEGFR-2 inhibitors, aryl hydrocarbon receptor agonists, indoleamine 2,3-dioxygenase, dendritic cells, regulatory T cells, immunomodulation, autoimmune disease, graft rejection, endogenous AhR ligands, xenobiotic-metabolizing enzymes, anticancer drug repurposing
MeSH terms
Adjuvants, Immunologic, Animals, Aryl Hydrocarbon Hydroxylases, Enzyme Induction, Indoles, Ligands, Pyrroles, Repressor Proteins, Spleen, Transcription, Genetic, CD4-Positive T-Lymphocytes, Up-Regulation, Point Mutation, Receptors, Aryl Hydrocarbon, Cytochrome P-450 CYP1A1, Receptors, Vascular Endothelial Growth Factor, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice, Forkhead Transcription Factors, Cytochrome P-450 CYP1B1

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