Vanadium Compounds as PTP Inhibitors

Abstract

Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

Keywords: BMOV; PTP; cancer; diabetes; oxidovanadium; oxovanadium; protein tyrosine phosphatases; vanadate; vanadium.

Figure 1

Protein tyrosine phosphatase (PTP) superfamily. Class 1-IV PTPs detailed in inner rings, with their substrate specificities stated in the outer ring.

Figure 2

Structure 1, orthovanadate; Structure 2, phosphate; Structure 3, bisperoxo(1,10-phenanthroline)oxidovanadate(V) (bpv-phen); Structure 4, decavanadate (V10); Structure 5, bis(maltolato)oxidovanadium (IV) (BMOV); Structure 6, bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxidovanadium(IV) (Metvan); Structure 7, vanadium(V) oxo phenolato complex [25].

Figure 3

Schematic of the ingestion, chemical dissociation and cellular targeting of a generic oxidovanadium complex. Complexes of oxidovanadium with organic ligands can have good bioavailability across the gut wall, but can dissociate rapidly in the gut and blood into constituent vanadate ions and ligand derivatives. At target cells the ligands may or may not enter cells, but intracellularly they can have significant cytotoxic effects. Similarly, vanadate will enter cells and have a range of effects including PTP inhibition. Some compounds may be very stable in the blood and these may enter cells intact, where they are thought to ultimately dissociate. Oxidovanadium and peroxidovanadium compounds can generate ROS in cells indirectly or directly, respectively. Such ROS can in turn inhibit PTPs, or cause non-specific cell damage. Note that the cell shown could also represent an off-target site where these chemicals have detrimental actions.