TY  - JOUR
ID  - pittir19915
UR  - http://d-scholarship-dev.library.pitt.edu/19915/
IS  - 3
A1  - Powis, G
A1  - Wipf, P
A1  - Lynch, SM
A1  - Birmingham, A
A1  - Kirkpatrick, DL
Y1  - 2006/03/01/
N2  - 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-1?, 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.
JF  - Molecular Cancer Therapeutics
VL  - 5
SN  - 1535-7163
TI  - Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase
SP  - 630 
AV  - public
EP  -  636
ER  -