title: Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor β.
abstract: Estrogen Receptor-β (ER-β), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA-methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT-inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT-inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-β. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-β (mRNA/protein). Bisulfite-sequencing of ER-β promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-β promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-β expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-β through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Nand
authors.initials: N
authors.lastname: Lal
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Saumya
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Konica
authors.initials: K
authors.lastname: Porwal
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Tara
authors.initials: T
authors.lastname: Rawat
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: J P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Singh
authors.initials: S
authors.lastname: Rajender
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: V L
authors.initials: VL
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India. g_gupta@cdri.res.in.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004221:Disulfiram / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C411744:DMAP1 protein, human; C000600034:ESR2 protein, human; D004791:Enzyme Inhibitors; D047629:Estrogen Receptor beta; D012097:Repressor Proteins; D004221:Disulfiram
keywords: DNMT1; cell proliferation; disulfiram; estrogen receptor-β; prostate cancer