Abstract
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.
Highlights
Selenocompounds (SeCs) refer to a broad category of selenium (Se)-containing chemicals
The selenocyanate compound p-XSC (p-xyleneselenocyanate) was shown to be highly toxic to the murine acute myeloid leukemia cell line C1498 in a concentration-dependent manner, while its cytotoxicity was completely abrogated after addition of 1% bovine serum albumin (BSA) in the complete medium (Figure 1b)
In order to investigate whether this pattern applied to other categories of SeCs, e.g., selenazolone, seleninic acid, and diselenide, we examined the cytotoxicity of ebselen, MeSeA, and CysSe2 on C1498 cells with or without 1% BSA (Figure 1e–g)
Summary
Selenocompounds (SeCs) refer to a broad category of selenium (Se)-containing chemicals. SeCs typically feature strong redox activity and could generate abundant reactive oxygen species (ROS) leading to induction of cell death, due to the Se element [1]. This trait is being extensively translated into cancer chemotherapy [2]. It is noteworthy that some types of cancer have been reported to be more susceptible to oxidative stress than normal cells [3,4]; SeCs hold the promise to outperform conventional chemotherapeutics in achieving targeted therapy [5]. Inspired by the promising effects of SeCs and in order to further improve their treatment efficacy, several researchers have started to introduce Se into current treatments, including both small molecules (i.e. aspirin and zidovudine) [9,10] and antibodies (trastuzumab and bevacizumab) [11]
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