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.

Molecular and Cellular Mechanisms of Cytotoxic Activity of Vanadium Compounds against Cancer Cells

“…Irving and et al [105] discussed the potential of vanadium derivatives as protein tyrosine phosphatases (PTP) enzyme inhibitors. Phosphotyrosine signaling is implicated in almost all aspects of cancer biology due to its widespread influence over cell signaling, and alterations brought about by mutations can drive the initiation and progression of many different tumor types [106].…”

“…Phosphotyrosine signaling is implicated in almost all aspects of cancer biology due to its widespread influence over cell signaling, and alterations brought about by mutations can drive the initiation and progression of many different tumor types [106]. It has been determined that various vanadium compounds were shown to be successful in inhibiting tumor development in animal models through their ability to inhibit PTPs and to induce oxidative damage, which itself likely contributes to PTP inhibition [105].…”

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

“…Vanadate is not a specific inhibitor of all phosphatases but can be a potent inhibitor of the activity, because it can mimic the 5-coordinate transition state of phosphate formed during the phosphatase catalytic cycle. Vanadate can also cause cysteine oxidation at the active site, thus, affecting the function of several PTPases that require thiol-reducing agents for optimal activity [221][222][223][224]. Likewise, it is accepted that during the dephosphorylation process, the cysteine of the active site is in the thiolate state (RS -) and very susceptible to oxidation.…”

Bis(maltolato)oxovanadium(IV) Induces Angiogenesis via Phosphorylation of VEGFR2

“…Vanadium compounds are a group of molecules that act as nonselective tyrosine phosphatase inhibitors [10]. Their mechanism of action, the inhibition of PTPs, was first shown on the insulin receptor where vanadium compounds act as insulin-mimic enhancing its phosphorylation [11,12].…”

“…In this context bis(maltolato)oxovanadium(IV) (BMOV) was shown to have antidiabetic properties and insulin-mimicking effects and to improve cardiac dysfunctions in diabetic models [13][14][15]. Previously used as simple inorganic vanadium salts, they were then replaced by larger and more complex compounds with organic ligands, that have shown increased bioavailability [10,16,17].…”