Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma

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.

3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells

“…First, BSO can potentiate anti-tumor effect of 3-BP by suppressing the antagonist to 3-BP, i.e., GSH. Previous studies showed that 3-BP occurred a significant decrease in GSH concentrations in multiple myeloma cells [39]. This phenomenon was occurred by the 3-BP-GSH binding to inactivate 3-BP [40].…”

“…The enzyme that has the ability to catalyze the conjugation of the reduced form of GSH to the substrates is glutathione S-transferase (GST). Previous study showed that the GST gene expression increases after 3-BP exposure to multiple myeloma cells [39]. In addition, it was reported that 3-BP alters the level of the expression of genes encoding other crucial enzymes involved in GSH metabolism such as rGCS and glutathione synthetase [39].…”

“…Previous study showed that the GST gene expression increases after 3-BP exposure to multiple myeloma cells [39]. In addition, it was reported that 3-BP alters the level of the expression of genes encoding other crucial enzymes involved in GSH metabolism such as rGCS and glutathione synthetase [39]. Given that GSH plays a role for attenuating oxidative stress in the cancer cell, any compounds which potentiate oxidative stress can reduce intracellular GSH levels.…”

3‐Bromopyruvate as a potent anticancer therapy in honor and memory of the late Professor André Goffeau

“…In the same year, Professor Goffeau organized a private international conference in Brussels to discuss preliminary results regarding 3 BP 's inhibitory effect on liver cancer (in vivo), on multiple myeloma (MM, in vitro), and also on the yeast Saccharomyces cerevisiae . The outcome of our collaborative team research resulted in a much better understanding of the mechanism of 3 BP 's anticancer effect on MM cells (Majkowska‐Skrobek et al, ; Niedźwiecka et al, ) and its inhibitory effect on microorganisms of the genus S . cerevisiae (Lis et al, ; Lis et al, ), Cryptococcus (Dyląg et al, ; Niedźwiecka et al, ), and Prototheca (Jagielski, Niedźwiecka, Roeske, & Dylag, ).…”

“…The outcome of our collaborative team research resulted in a much better understanding of the mechanism of 3 BP 's anticancer effect on MM cells (Majkowska‐Skrobek et al, ; Niedźwiecka et al, ) and its inhibitory effect on microorganisms of the genus S . cerevisiae (Lis et al, ; Lis et al, ), Cryptococcus (Dyląg et al, ; Niedźwiecka et al, ), and Prototheca (Jagielski, Niedźwiecka, Roeske, & Dylag, ). One significant observation made during our collaboration was that 3 BP induces oxidative stress in Cryptococcus neoformans and MM cancer cells.…”