eprintid: 19915 rev_number: 16 userid: 1419 dir: disk0/00/01/99/15 datestamp: 2013-10-30 16:53:17 lastmod: 2019-02-02 15:57:01 status_changed: 2013-10-30 16:53:17 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Powis, G creators_name: Wipf, P creators_name: Lynch, SM creators_name: Birmingham, A creators_name: Kirkpatrick, DL creators_email: creators_email: pwipf@pitt.edu creators_email: creators_email: creators_email: creators_id: creators_id: PWIPF creators_id: creators_id: creators_id: title: Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase ispublished: pub divisions: sch_as_chemistry full_text_status: public 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. date: 2006-03-01 date_type: published publication: Molecular Cancer Therapeutics volume: 5 number: 3 pagerange: 630 - 636 refereed: TRUE issn: 1535-7163 id_number: 10.1158/1535-7163.MCT-05-0487 other_id: NLM NIHMS8948 other_id: NLM PMC1462925 pmcid: PMC1462925 pmid: 16546977 mesh_headings: Animals mesh_headings: Antineoplastic Agents--pharmacology mesh_headings: Cell Line, Tumor mesh_headings: Dioxanes--chemistry mesh_headings: Dioxanes--pharmacokinetics mesh_headings: Dioxanes--pharmacology mesh_headings: Enzyme Inhibitors--pharmacology mesh_headings: Glycine--analogs & derivatives mesh_headings: Glycine--chemistry mesh_headings: Glycine--pharmacokinetics mesh_headings: Glycine--pharmacology mesh_headings: Humans mesh_headings: Hypoxia-Inducible Factor 1, alpha Subunit--antagonists & inhibitors mesh_headings: Mice mesh_headings: Naphthalenes mesh_headings: Neoplasms--enzymology mesh_headings: Spiro Compounds--chemistry mesh_headings: Spiro Compounds--pharmacology mesh_headings: Thioredoxin Reductase 1 mesh_headings: Thioredoxin-Disulfide Reductase--antagonists & inhibitors mesh_headings: Vascular Endothelial Growth Factor A--antagonists & inhibitors mesh_headings: Xenograft Model Antitumor Assays chemical_names: Antineoplastic Agents chemical_names: Dioxanes chemical_names: Enzyme Inhibitors chemical_names: HIF1A protein, human chemical_names: Hypoxia-Inducible Factor 1, alpha Subunit chemical_names: Naphthalenes chemical_names: PX 916 chemical_names: Spiro Compounds chemical_names: Vascular Endothelial Growth Factor A chemical_names: palmarumycin CP(1) chemical_names: Glycine chemical_names: TXNRD1 protein, human chemical_names: Thioredoxin Reductase 1 chemical_names: Thioredoxin-Disulfide Reductase chemical_names: Txnrd1 protein, mouse citation: 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 document_url: http://d-scholarship-dev.library.pitt.edu/19915/1/licence.txt