4.3. Therapeutic applications of arsenic binding to proteins

Arsenous acid [As(OH)3] formed by dissolving of arsenic trioxide (As2O3) was found to be an effective and safe treatment for acute promyelocytic leukemia (APL) in the 1970s. The United States Food and Drug Administration approved the use of As2O3 as a treatment for APL in September 2000 [50]. As2O3 treatment was shown to have a dual effect on APL cells, with low arsenic concentration (0.25–0.50 mM) favoring APL cell differentiation and high concentrations (1–2 mM) inducing apoptosis (programmed cell death). Direct arsenic binding to cysteine residues present in zinc fingers of promyelocytic leukemia fusion protein (PML-RARa) was found to be a mechanism underlying APL remission [51]. Arsenic binding induces a conformational change in the structure of the protein (PML-RARa), facilitating its oligomerization. This oligomerization enhances ubiquitylation and SUMOylation, resulting in its degradation [52]. Given the constant requirement for DNA and protein synthesis, thioredoxin (Trx) and thioredoxin reductase (TrxR) are observed to be overexpressed in various tumors. Moreover, in vivo data suggests that TrxR is necessary for the growth of tumor cells, making them plausible targets for anticancer therapies [53].

Arsenic has been proposed to induce cell death through thioredoxin reductase (TrxR) inhibition, with both N-terminal dithiols and C-terminal selenothiol interacting with arsenic compound [54]. Sensitivity of cells to arsenic can be attributed to high expression of membrane transporter aquaglyceroporin which allows arsenite uptake, along with a low, basal level of cellular glutathione. Multiple factors such as liver damage, cardiac toxicity and peripheral neuropathies caused by toxicity at higher dosage of As2O3, along with bioavailability of arsenic compounds, limit the widespread use of As2O3 against solid tumors [50].
