Abstract
Dithiocarbamate compound Disulfiram (DSF) that binds with copper and functions as an inhibitor of aldehyde dehydrogenase is a Food and Drug Administration approved agent for treatment of alcoholism. Copper complexed DSF (DSF-Cu) also possesses anti-tumor and chemosensitizing properties; however, its molecular mechanisms of action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF-Cu and the molecular mechanisms involved. DSF-Cu inhibited growth of the murine as well as human MPM cells in part by increasing levels of ubiquitinated proteins. DSF-Cu exposure stimulated apoptosis in MPM cells that involved activation of stress-activated protein kinases (SAPKs) p38 and JNK1/2, caspase-3, and cleavage of poly-(ADP-ribose)-polymerase, as well as increased expression of sulfatase 1 and apoptosis transducing CARP-1/CCAR1 protein. Gene-array based analyses revealed that DSF-Cu suppressed cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF inhibited MPM cell growth and survival by upregulating cell cycle inhibitor p27Kip1, IGFBP7, and inhibitors of NF-κB such as ABIN 1 and 2 and Inhibitory κB (IκB)α and β proteins. DSF-Cu promoted cleavage of vimentin, as well as serine-phosphorylation and lysine-63 linked ubiquitination of podoplanin. Administration of 50 mg/kg DSF-Cu by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo. Although podoplanin expression often correlates with metastatic disease and poor prognosis, phosphorylation of serines in cytoplasmic domain of podoplanin has recently been shown to interfere with cellular motility and migration signaling. Post-translational modification of podoplanin and cleavage of vimentin by DSF-Cu underscore a metastasis inhibitory property of this agent and together with our in vivo studies underscore its potential as an anti-MPM agent.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive malignancy that is associated with past asbestos exposure
Since the MPM cells utilized here are representative of the epitheliod (H2461 and H2595), sacromatoid (H2373), and biphasic (H2452) tumor histologic origins [17,25], and the treatments with DSF-Cu significantly inhibited viabilities of most of these cells, the data would suggest for potential utility of this agent to target a diverse histotypes of MPM tumors
Consistent with emerging anti-cancer potential of DSF-Cu, our current studies revealed that DSF-Cu inhibits growth of a number of MPM cells
Summary
Malignant pleural mesothelioma (MPM) is an aggressive malignancy that is associated with past asbestos exposure. Millions of workers in the US and world over have been exposed to asbestos, and exposure to asbestos has been shown to increase the risk of several serious diseases including asbestosis, lung cancer and MPM [1]. It is estimated that there are 2,000 to 3,000 people diagnosed with MPM each year in the United States and the incidence of this disease is expected to increase in the decade in United States and Europe [3,4]. MPM is highly resistant to conventional therapies that consist of multimodality treatment involving surgery, adjuvant or neoadjuvant chemotherapy, and radiation [2]. The median survival of MPM is about 9–17 months [3], and coupled with its increasing incidence and resistance to currently available chemotherapies, development of new treatments for MPM is urgently needed
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