A Short‐Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections

Abstract

The chemistry and short lifetimes of metal‐based anti‐cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1L2], where L1 is N‐(salicylideneaminato)‐N′‐(2‐hydroxyethyl)ethane‐1,2‐diamine and L2 is 3,5‐di‐tert‐butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8‐fold less toxic. 1 was 12‐fold more toxic than cisplatin in T98g cells and 6‐fold more toxic in T98g cells than in a non‐cancer human cell line, HFF‐1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal‐binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

Vanadium(V/IV)–Transferrin Binding Disrupts the Transferrin Cycle and Reduces Vanadium Uptake and Antiproliferative Activity in Human Lung Cancer Cells

“…In contrast to suggestions in the literature, ,, V­(V/IV)–Tf binding prevents cellular V uptake through the Tf–TfR1 uptake pathway under normoxic conditions, due to the inability of V­(V/IV)–Tf to complete the Tf cycle, although this does not exclude the role of V­(III)–Tf formed under hypoxic and/or reducing conditions. , A decrease in V­(V/IV) cellular uptake in the presence of Tf leads to a dramatic decrease in its antiproliferative activity. This factor has to be taken into account in the development of medicinal V­(V) and V­(IV) complexes, ,− since such complexes are likely to dissociate fully or partially in the blood with the formation of V­(V/IV)–Tf adducts. − , The development of metal complexes that can withstand the protein binding in an extracellular environment to enable them to enter cells intact and to release active components within the cells is a likely prerequisite to their anticancer activity. ,, An improved understanding of the roles of V­(V/IV) binding to Tf and other biomolecules is required to facilitate the development of promising novel applications of V­(V/IV) complexes, including activation of oncolytic viruses, , treatment of neurodegenerative disorders, , and intratumoral injections for the treatment of unresectable cancers …”

“…13,78,80 An improved understanding of the roles of V(V/IV) binding to Tf and other biomolecules is required to facilitate the development of promising novel applications of V(V/IV) complexes, including activation of oncolytic viruses, 83,84 treatment of neurodegenerative disorders, 85,86 and intratumoral injections for the treatment of unresectable cancers. 87 ■ ASSOCIATED CONTENT * sı Supporting Information…”

Biological Consequences of Vanadium Effects on Formation of Reactive Oxygen Species and Lipid Peroxidation

“…One class of compounds is vitamin E chelate siderophores with a lipid portion and a metal ion, amphiphilic properties and hydrolytic stability [ 15 ]. The other class of compounds are vanadium complexes with a sterically hindered catechol that have low toxicity while remaining reactive, suggesting that such vanadium compounds may be active as LPO inducers and, in the case of this latter complex, demonstrate some efficacy against cancer cells [ 95 , 96 ].…”

Mono Versus Dinuclear Vanadium(V) Complexes: Solvent Dependent Structural Versatility and Electro Syntheses of Mixed-Valence Oxovanadium(IV/V) Entities in Solution

“…The coordination chemistry of vanadium has provided an impetus in a variety of catalytic processes, 1−4 biochemical processes such as peroxidase mimicking activity, 5 insulin mimicking activities, 6 cytotoxic activities, 7 nitrogen fixation, 8 haloperoxidation, 9 epoxidation, 10 inhibition of phosphatemetabolizing enzymes, 11 alleviation of diabetes mellitus symptoms 12 and so on. Besides this, the literature reveals oxidovanadium complexes of salicylaldimine and salicylaldehyde-hydrazones as potential anti-cancer drugs 13 for brain cancer treatment, 8-hydroxyquinoline vanadium complexes as anti-tuberculosis and anti-proliferative metallodrug. 14a So, vanadium chemistry has certainly attracted medicinal attention.…”