Extracellular Albumin Covalently Sequesters Selenocompounds and Determines Cytotoxicity

Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the treatment efficacy of drugs. In the present investigation, we hypothesized that extracellular albumin might orchestrate SeCs efficacy. Four SeCs representing distinct categories were selected to investigate their cytotoxicity, cellular uptake, and species transformation. Concomitant treatment of albumin greatly decreased cytotoxicity and cellular uptake of SeCs. Using both X-ray absorption spectroscopy and hyphenated mass spectrometry, we confirmed the formation of macromolecular conjugates between SeCs and albumin. Although the conjugate was still internalized, possibly via albumin scavenger receptors expressed on the cell surface, the uptake was strongly inhibited by excess albumin. In summary, the present investigation established the importance of extracellular albumin binding in determining SeCs cytotoxicity. Due to the fact that albumin content is higher in humans and animals than in cell cultures, and varies among many patient categories, our results are believed to have high translational impact and clinical implications.