title: Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis.
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.
authors.affiliation: Department of Oncology, Wayne State University, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
authors.forename: Vino T
authors.initials: VT
authors.lastname: Cheriyan
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, Wayne State University, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
authors.forename: Magesh
authors.initials: M
authors.lastname: Muthu
authors.affiliation: Department of Oncology, Wayne State University, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
authors.forename: Shazia
authors.initials: S
authors.lastname: Jamal
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Life Science and Engineering, Harbin Institute of Technology, Harbin, China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Polin
authors.affiliation: Department of Computer Science, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
authors.affiliation: Division of Cardiothoracic Surgery, New York University Cancer Center, New York, New York, United States of America.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Wali
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004221:Disulfiram / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D053148:Caspase 3; D004221:Disulfiram