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Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase

Powis, G and Wipf, P and Lynch, SM and Birmingham, A and Kirkpatrick, DL (2006) Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase. Molecular Cancer Therapeutics, 5 (3). 630 - 636. ISSN 1535-7163

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Abstract

The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxia-inducible factor-1α, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth. Copyright © 2006 American Association for Cancer Research.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Powis, G
Wipf, Ppwipf@pitt.eduPWIPF
Lynch, SM
Birmingham, A
Kirkpatrick, DL
Date: 1 March 2006
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 5
Number: 3
Page Range: 630 - 636
DOI or Unique Handle: 10.1158/1535-7163.mct-05-0487
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Animals; Antineoplastic Agents--pharmacology; Cell Line, Tumor; Dioxanes--chemistry; Dioxanes--pharmacokinetics; Dioxanes--pharmacology; Enzyme Inhibitors--pharmacology; Glycine--analogs & derivatives; Glycine--chemistry; Glycine--pharmacokinetics; Glycine--pharmacology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit--antagonists & inhibitors; Mice; Naphthalenes; Neoplasms--enzymology; Spiro Compounds--chemistry; Spiro Compounds--pharmacology; Thioredoxin Reductase 1; Thioredoxin-Disulfide Reductase--antagonists & inhibitors; Vascular Endothelial Growth Factor A--antagonists & inhibitors; Xenograft Model Antitumor Assays
Other ID: NLM NIHMS8948, NLM PMC1462925
PubMed Central ID: PMC1462925
PubMed ID: 16546977
Date Deposited: 30 Oct 2013 16:53
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/19915

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