Encapsulating drug complexes also means that degradation in the circulation can be reduced, further concentrating the amount of active complex reaching the target tissue. 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. cell survival, making them potential malignancy drug targets [61]. A number of oncogenic PTPs have now been explained, the first of which was SHP2. Overexpression of SHP2 has been reported in leukaemia and breast cancer, and activating mutations are associated with childhood malignancies [62,63,64]. In breast cancer cell lines, shRNA-mediated inhibition of SHP2 reversed epithelial-to-mesenchymal transition and reduced migration and invasion [65]. Other PTPs such as PTP1b are also considered oncogenic in breast cancer models [66,67,68]. With the above in mind, there is now increasing interest in the development and use of PTP inhibitors for anti-cancer therapeutics. Vanadium-based chemicals may represent one source of these. 5.2. Anti-Cancer Activity of Vanadium Vanadium has long been of interest in cancer biology, with the first report of its ATN-161 anticancer activity in 1965 [69]. Since then considerable research efforts have described the potential for vanadium-based compounds in preventing the onset of tumourigenesis and in the treatment of cancers. Vanadium compounds are able to inhibit cancer initiation and progression in model systems by acting against several of Weinbergs hallmarks of cancer, including inducing apoptosis or other cell death pathways, reducing proliferation and inhibiting migration and metastasis [70]. The most successful cancer therapies are those that target more than one aspect of tumour biology, therefore vanadium-derived chemicals are seemingly very promising, multifunctional therapeutic candidates. In Table 1 and Table 2 we summarize several studies reporting anti-cancer properties of a variety of vanadium ATN-161 compounds, both in vivo and in vitro. Table 1 Summary of some reported anti-cancer activities of vanadium in cancer cell lines. [4,28,29]. These findings suggest that decavanadates, like other oxidovanadium complexes, may have significant systemic toxicities if they were to be used as therapeutic compounds. Although the mitochondrial effects described above appear to be specific to decavanadate, they cannot be entirely discounted with respect to monomeric vanadium complexes as there is some evidence suggesting that decavanadate Rabbit Polyclonal to RIPK2 may be formed from vanadate and stabilized within cells ATN-161 [31,116]. As discussed previously, conversion from vanadyl to vanadate generates ROS [21]. This increase in ROS may contribute to PTP inhibition; however, it may also contribute to cell death described in some of the in vitro anti-cancer studies. Cancer cells often exist in a state of sub-lethal oxidative stress, thus even small increases in ROS may have dramatic effects on tumour cell viability by damaging DNA and lipids. Some vanadium compounds, in particular vanadocenes, can complex with DNA and inhibit RNA and DNA synthesis, likely contributing to their anticancer efficacy [117,118]. 5.4. Systemic Toxicities Associated with Vanadium When administered orally, vanadium enters the circulation via absorption from the GI tract. Once in the bloodstream, vanadium compounds undergo ligand exchange, and can become bound to metabolites such as lactate and citrate, and proteins, predominantly transferrin [16,119]. Vanadium can enter cells from the bloodstream via passive diffusion depending on the ligation of vanadium, active transport through anion channels and possibly by endocytosis in the case of transferrin-bound vanadium [3,120]. The relative abundance of vanadium in specific tissues is as follows; bone kidney, liver blood muscle brain [34,82]. Unabsorbed vanadium exits the body in faeces, whereas absorbed vanadium is eventually cleared in urine and from hair and skin loss. A small proportion accumulates in high phosphate tissues such as the bone for long periods of time [32,57]. As mentioned previously, this presents a potential safety concern in administering oxidovanadium as a therapeutic. Although vanadium has not been classified by the International Agency for Research on Cancer (IARC) as a carcinogen, there have been some reports that vanadium compounds can induce tumourigenesis, potentially due to increased ROS production [19]. A study by Ress et al. sought to identify toxicity associated with long term exposure to airborne vanadium pentoxide in mice.