Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase.
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.
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, FC-6.3044, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. gpowis@mdanderson.org
Garth
G
Powis
Peter
P
Wipf
Stephen M
SM
Lynch
Anne
A
Birmingham
D Lynn
DL
Kirkpatrick
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004146:Dioxanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D051379:Mice; D009281:Naphthalenes; D009369:Neoplasms / Q000201:enzymology*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004146:Dioxanes; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009281:Naphthalenes; C510477:PX 916; D013141:Spiro Compounds; D042461:Vascular Endothelial Growth Factor A; C422643:palmarumycin CP(1); C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase; C516125:Txnrd1 protein, mouse; D005998:Glycine