title: Glutathione S-transferase P1-1 as a target for mesothelioma treatment.
abstract: Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum(II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO-211H, MPP89, MM-B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC(50) values in the low micromolar range (IC(50) between 1 and 4 μM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy.
authors.affiliation: Department of Chemical Sciences and Technologies, University of Tor Vergata, Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellizzari Tregno
authors.forename: Andrea
authors.initials: A
authors.lastname: Sau
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.forename: Camilla
authors.initials: C
authors.lastname: Palumbo
authors.forename: Angela
authors.initials: A
authors.lastname: Alama
authors.forename: Rosella
authors.initials: R
authors.lastname: Cicconi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Anna M
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D061986:MCF-7 Cells; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C528479:6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol; D010069:Oxadiazoles; D051549:Glutathione S-Transferase pi; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide