Redox homeostasis is especially important in the brain where high oxygen consumption produces an abundance of harmful oxidative by-products.
Glutathione (GSH) is a tripeptide non-
protein thiol. It is the central nervous system's most abundant
antioxidant and the master controller of brain redox homeostasis. The
glutamate transporters, System xc(-) (SXC) and the
Excitatory Amino Acid Transporters (EAAT), play important, synergistic roles in the synthesis of GSH. In glial cells, SXC mediates the uptake of
cystine, which after intracellular reduction to
cysteine, reacts with
glutamate during the rate-limiting step of GSH synthesis. EAAT3 mediates direct
cysteine uptake for neuronal GSH synthesis. SXC and EAAT work in concert in glial cells to provide two intracellular substrates for GSH synthesis,
cystine and
glutamate. Their cyclical basal function also prevents a buildup of extracellular
glutamate, which SXC releases extracellularly in exchange for
cystine uptake. Maintaining extracellular
glutamate homeostasis is critical to prevent neuronal toxicity, as well as
glutamate-mediated SXC inhibition, which could lead to a depletion of intracellular GSH and loss of cellular redox control. Many neurological diseases show evidence of GSH dysfunction, and increased GSH has been widely associated with
chemotherapy and
radiotherapy resistance of
gliomas. We present evidence suggesting that
gliomas expressing elevated levels of SXC are more reliant on GSH for growth and survival. They have an increased inherent radiation resistance, however, inhibition of SXC can increase
tumor sensitivity at low radiation doses. GSH depletion through SXC inhibition may be a viable mechanism to enhance current
glioma treatment strategies and make
tumors more sensitive to radiation and
chemotherapy protocols.