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

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-1alpha, 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.

• Authors: Garth Powis, Peter Wipf, Stephen M Lynch, Anne Birmingham, D Lynn Kirkpatrick
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 3 Pg. 630-6 (Mar 2006) ISSN: 1535-7163 [Print] United States
• PMID: 16546977 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Dioxanes
• Enzyme Inhibitors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Naphthalenes
• PX 916
• Spiro Compounds
• Vascular Endothelial Growth Factor A
• palmarumycin CP(1)
• TXNRD1 protein, human
• Thioredoxin Reductase 1
• Thioredoxin-Disulfide Reductase
• Txnrd1 protein, mouse
• Glycine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Dioxanes (chemistry, pharmacokinetics, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glycine (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors)
• Mice
• Naphthalenes
• Neoplasms (enzymology)
• Spiro Compounds (chemistry, pharmacology)
• Thioredoxin Reductase 1
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Xenograft Model Antitumor Assays