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Abstract
In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death.
Highlights
3-bromopyruvate (3BP) is a highly promising anticancer and antifungal drug [1, 2]
GSH contains a very reactive thiol group (-SH) which makes it a major cellular antioxidant [12]. It seems that GSH is involved in the repair of DNA as the accumulation of DNA damage was observed in organs of mice that exhibit a defect in GSH metabolism that causes a decrease in the concentration of GSH [13]
In the presence of 5 mM GSH in synthetic medium (SD) medium containing 3BP at a concentration equal to the Minimal Inhibitory Concentration (MIC) value (0.2 mM) for the most resistant strain of Cryptococcus neoformans, the growth of all tested Cryptococcus neoformans strains was restored to that observed for the growth control (Figure 1a)
Summary
3-bromopyruvate (3BP) is a highly promising anticancer and antifungal drug [1, 2]. Its activity is primarily based on the inhibition of pivotal enzymes of glycolysis, e.g., hexokinase-2, glyceraldehyde-3phosphate dehydrogenase (GAPDH) [3, 4], and lactate dehydrogenase [4, 5]. The efficiency of 3BP is clearly dependent on the intracellular level of GSH, and it is not surprising that this agent exhibits a synergistic effect with the known GSH depletors including such compounds as buthionine sulphoximine (BSO), methionine sulfoximine (MSO) and paracetamol (acetaminophen). It is well known for mammalian cells that all of these compounds act as GSH depletors [16,17,18]. The important role of GSH is not questionable, it should be noted as previously described that differences in 3BP transport into cells of species differentiated fungi are related directly to observed differences in their susceptibility to this compound [15]
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