Abstract
Abstract Disulfiram (DSF) is a member of the dithiocarbamate family of compounds that bind with copper and function as inhibitor of aldehyde dehydrogenase. DSF is one of the drugs approved by Food and Drug Administration for treatment of alcoholism. Recent studies have indicated anti-tumor and chemosensitizing properties of DSF. However, the molecular mechanisms of DSF action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF and the molecular mechanisms involved. DSF inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in accumulation of ubiquitinated proteins. DSF suppression of MPM growth also involved elevated apoptosis as evidenced by activation of caspase-3, elevated levels of pro-apoptotic Bax protein and cleavage of poly-(ADP-ribose)-polymerase. Our studies including gene-array based analyses further revealed that DSF suppressed a number of cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF treatments also stimulated expression of sulfatase 1, growth arrest-specific (GAS) 6 protein, and CARP-1/CCAR1, a novel transducer of cell growth signaling. Administration of 50mg/kg DSF by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating cell growth arrest and apoptosis. Together our in vitro and in vivo studies suggest that DSF suppresses MPM growth by targeting multiple pathways that include blockage of metastasis signaling and stimulation of apoptosis, and thus holds promise as an anti-MPM agent. Citation Format: Ying Wang, Vino T. Cheryan, Shazia Jamal, Di Chen, Huanjie Yang, Lisa A. Polin, Harvey I. Pass, Q Ping Dou, Sunita Sharma, Arun K. Rishi, Anil Wali. Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2013-5564
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