Vanadium(V) tris-3,5-di-tert-butylcatecholato complex: Links between speciation and anti-proliferative activity in human pancreatic cancer cells

摘要

Vanadium complexes are intensively tested for anti-cancer activities, particularly for the novel treatment protocols involving injections of cytotoxic compounds directly into the tumor. This approach is increasingly applied to difficult-to-treat cancers, such as pancreatic cancer. The first study of in-vitro anti-cancer properties of a rare stable non-oxido V(V) complex, (NH4)[V(dtbc)(3)], where dtbcH(2) is 3,5-di-tert-butylcatechol, was performed by a combination of end-point viability assays and real-time (IncuCyte) proliferation and cytotoxicity assays in human pancreatic cancer (PANC-1) cells. An improved synthetic procedure led to a nearly quantitative yield of the complex under ambient conditions. Reactions of (NH4)IV(dtbc)(3)] either in polar organic solvents or in neutral aqueous media led to the formation of V(V)-oxido-catecholato intermediates (characterized by electrospray mass spectrometry) that were responsible for its anti-proliferative and cytotoxic (apoptotic or necrotic) activity (IC50, 3.5-18 mu M V in 72 h assays). These results demonstrate the link between solution speciation and biological activity of V complexes. Reaction of (NH4)[V(dtbc)(3)] with human serum albumin (HSA) in aqueous media led to the formation of protein-bound V(V) oxido-catecholato species that showed high anti-proliferative activity (IC50 similar to 10 mu M V) combined with low cytotoxicity. Formation of HSA adducts of hydrophobic V complexes, such as (NH4)[V(dtbc)(3)], is a promising way to achieve their sustained delivery to cancer tumors.