Redox Mechanisms in Cisplatin Resistance of Cancer Cells: The Twofold Role of Gamma-Glutamyltransferase 1 (GGT1)

Cisplatin (CDDP) is currently employed for the treatment of several solid tumors, but cellular heterogeneity and the onset of drug resistance dictate that suitable biomarkers of CDDP sensitivity are established. Studies on triple-negative breast cancer (TNBC) have recently confirmed the involvement...

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Bibliographic Details
Published in:Frontiers in oncology 2022-05, Vol.12, p.920316-920316
Main Authors: Pompella, Alfonso, Corti, Alessandro, Visvikis, Athanase
Format: Article
Language:English
Subjects:
biomarkers
Cancer
cisplatin
drug resistance
gamma-glutamyltransferase (GGT)
glutathione
Life Sciences
Oncology
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Summary:Cisplatin (CDDP) is currently employed for the treatment of several solid tumors, but cellular heterogeneity and the onset of drug resistance dictate that suitable biomarkers of CDDP sensitivity are established. Studies on triple-negative breast cancer (TNBC) have recently confirmed the involvement of gamma-glutamyltransferase 1 (GGT1), whose enzyme activity expressed at the cell surface favors the cellular resupply of antioxidant glutathione (GSH) thus offering cancer cells protection against the prooxidant effects of CDDP. However, an additional well-established mechanism depends on GGT1-mediated matabolism of extracellular GSH. It was in fact shown that glycyl-cysteine - the dipeptide originated by GGT1-mediated GSH metabolism at the cell surface - can promptly form adducts with exogenous CDDP, thus hindering its access to the cell, interactions with DNA and overall cytotoxicity. Both mechanisms: mainainance of intracellular GSH levels extracellular CDDP detoxication are likely concurring to determine GGT1-dependent CDDP resistance.
ISSN:2234-943X
2234-943X
DOI:10.3389/fonc.2022.920316