Cancer Sci. 2012 Nov 5. doi: 10.1111/cas.12061. [Epub ahead of print]
Glutathione S-transferase P1-1 as a target for Mesothelioma treatment.
Source
Department of Chemical Sciences and Technologies, University of 'Tor Vergata', Rome, Italy.
Abstract
Malignant Pleural Mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase (GST), which catalyzes the conjugation between GSH and platinum(II)-containing drugs. Therefore, we decided to evaluate 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 the sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused a 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 resulted comparable or even higher than 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, might be a promising new strategy for treating this rare and aggressive malignancy.
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