It is predicted that the incidence of mesothelioma will increase and thus it is important to find new ways to treat this chemoresistant tumor. Glutathione-S-Transferase pi (GST pi) is found at significant levels in mesotheliomas and thus attenuating its intracellular levels may provide a means of sensitizing mesothe- lioma cells to chemotherapy. GST pi knockdowns were therefore prepared with shRNA (less off-target effects) employing two cell lines (211H, H2452) that were typed by immunohistochemistry to be of mesothelial origin. The knockdowns exhibited a decrease in both total GST enzyme activity and GST pi protein levels as well as an increase in both glutathione levels and sensitivity to cis and oxaliplatin. Cisplatin treatment of the knockdowns increased ROS levels significantly (as compared to the parental cells) and produced activation of the JNK/p38 pathways and activating transcription factor (ATF2). The degree of activation and increase in ROS appeared to correlate with the cell line's sensitivity to cisplatin. Treatment with N-Acetyl Cysteine decreased ROS production and JNK/p38 phosphorylation but had minimal affect on ATF2 suggesting a direct interaction of GTP pi with this transcription factor. Oxaliplatin treatment produced only minimal changes in ROS levels and activation of the JNK/p38 pathway. Recently, new methods of siRNA delivery (nanoparticles) have been shown to be effective in decreasing the levels of target proteins in humans including candidate genes involved in drug resistance thus this approach may have promise in sensitizing cisplatin-resistant tumors to chemotherapy. (C) 2014 Elsevier Inc. All rights reserved.