TY - JOUR
T1 - The cystine/cysteine cycle and GSH are independent and crucial antioxidant systems in malignant melanoma cells and represent druggable targets
AU - Venè, Roberta
AU - Castellani, Patrizia
AU - Delfino, Laura
AU - Lucibello, Maria
AU - Ciriolo, Maria Rosa
AU - Rubartelli, Anna
PY - 2011/11/1
Y1 - 2011/11/1
N2 - 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 As 2O 3 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 As 2O 3. 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 As 2O 3 sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As 2O 3 may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended.
AB - 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 As 2O 3 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 As 2O 3. 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 As 2O 3 sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As 2O 3 may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended.
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U2 - 10.1089/ars.2010.3830
DO - 10.1089/ars.2010.3830
M3 - Article
C2 - 21529243
AN - SCOPUS:80053037896
VL - 15
SP - 2439
EP - 2453
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
SN - 1523-0864
IS - 9
ER -