relation: http://d-scholarship-dev.library.pitt.edu/19915/
title: Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase
creator: Powis, G
creator: Wipf, P
creator: Lynch, SM
creator: Birmingham, A
creator: Kirkpatrick, DL
description: 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
type: Article
type: PeerReviewed
format: text/plain
language: en
rights: attached
identifier: http://d-scholarship-dev.library.pitt.edu/19915/1/licence.txt
identifier:   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     
relation: 10.1158/1535-7163.MCT-05-0487