The Cystine/Cysteine Cycle and GSH Are Independent and Crucial Antioxidant Systems in Malignant Melanoma Cells and Represent Druggable Targets

Abstract

Aims: Cancer chemoresistance is often due to upregulation of antioxidant systems. Therapeutic targeting of these systems is however hampered by their redundancy. Here, we have performed a functional dissection of the antioxidant systems in different melanoma cases aimed at the identification of the most effective redox active drug. Results: We have identified two crucial antioxidant mechanisms: glutathione (GSH), the major intracellular redox buffer, and the cystine/cysteine cycle, which switches the extracellular redox state from an oxidized to a reduced state. The two mechanisms are independent in melanoma cells and may be substitutes for each other, but targeting both of them is lethal. Exposure to the pro-oxidant compound As₂O₃ induces an antioxidant response. However, while in these cells the intracellular redox balance remains almost unaffected, a reduced environment is generated extracellularly. GSH depletion by buthioninesulfoximine (BSO), or cystine/cysteine cycle inhibition by (S)-4-carboxyphenylglycine (sCPG), enhanced the sensitivity to As₂O₃. Remarkably, sCPG also prevented the remodeling of the microenvironment redox state. Innovation: We propose that the definition of the prevalent antioxidant system(s) in tumors is crucial for the design of tailored therapies involving redox-directed drugs in association with pro-oxidant drugs. Conclusion: In melanoma cells, BSO is the best enhancer of As₂O₃ sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As₂O₃ may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended. Antioxid. Redox Signal. 15, 2439–2453.