Substitution Kinetics, Albumin and Transferrin Affinities, and Hypoxia All Affect the Biological Activities of Anticancer Vanadium(V) Complexes
Aviva Levina, Canan Uslan, Heide A. Murakami, Debbie C. Crans, Peter A. Lay
Abstract
Limited stability of most transition-metal complexes in biological media has hampered their medicinal applications but also created a potential for novel cancer treatments, such as intratumoral injections of cytotoxic but short-lived anticancer drugs. Two related V(V) complexes, [VO(Hshed)(dtb)] ( 1 ) and [VO(Hshed)(cat)] ( 2 ), where H 2 shed = N -(salicylideneaminato)- N′ -(2-hydroxyethyl)-1,2-ethanediamine, H 2 dtb = 3,5-di- tert -butylcatechol, and H 2 cat = 1,2-catechol, decomposed within minutes in cell culture medium at 310 K ( t 1/2 = 43 and 9 s for 1 and 2, respectively). Despite this, both complexes showed high antiproliferative activities in triple-negative human breast cancer (MDA-MB-231) cells, but the mechanisms of their activities were radically different. Complex 1 formed noncovalent adducts with human serum albumin, rapidly entered cells via passive diffusion, and was nearly as active in a short-term treatment (IC 50 = 1.9 ± 0.2 μM at 30 min) compared with a long-term treatment (IC 50 = 1.3 ± 0.2 μM at 72 h). The activity of 1 decreased about 20-fold after its decomposition in cell culture medium for 30 min at 310 K. Complex 2 showed similar activities (IC 50 ≈ 12 μM at 72 h) in both fresh and decomposed solutions and was inactive in a short-term treatment. The activity of 2 was mainly due to the reactions among V(V) decomposition products, free catechol, and O 2 in cell culture medium. As a result, the activity of 1 was less sensitive than that of 2 to the effects of hypoxic conditions that are characteristic of solid tumors and to the presence of apo-transferrin that acts as a scavenger of V(V/IV) decomposition products in blood serum. In summary, complex 1, but not 2, is a suitable candidate for further development as an anticancer drug delivered via intratumoral injections. These results demonstrate the importance of fine-tuning the ligand properties for the optimization of biological activities of metal complexes.