PMID- 26599461
OWN - NLM
STAT- MEDLINE
DCOM- 20170517
LR  - 20170517
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 55
IP  - 11
DP  - 2016 Nov
TI  - 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 beta.
PG  - 1843-1857
LID - 10.1002/mc.22433 [doi]
AB  - Estrogen Receptor-beta (ER-beta), 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-beta. 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-beta (mRNA/protein). Bisulfite-sequencing of 
      ER-beta promoter revealed that compound-339 demethylated CpG sites more 
      efficaciously than DSF, restoring near-normal methylation status of ER-beta 
      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-beta 
      expression. Apparently both compounds inhibit prostate cancer cell proliferation 
      by re-expressing the epigenetically repressed tumor-suppressor ER-beta through 
      inhibition of DNMT activity. Compound-339 presents a new lead for further study 
      as an anti-prostate cancer agent. (c) 2015 Wiley Periodicals, Inc.
CI  - (c) 2015 Wiley Periodicals, Inc.
FAU - Sharma, Vikas
AU  - Sharma V
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Verma, Vikas
AU  - Verma V
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Lal, Nand
AU  - Lal N
AD  - Division of Medicinal and Process Chemistry, CSIR-Central Drug Research 
      Institute, Lucknow, India.
FAU - Yadav, Santosh K
AU  - Yadav SK
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Sarkar, Saumya
AU  - Sarkar S
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Mandalapu, Dhanaraju
AU  - Mandalapu D
AD  - Division of Medicinal and Process Chemistry, CSIR-Central Drug Research 
      Institute, Lucknow, India.
FAU - Porwal, Konica
AU  - Porwal K
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Rawat, Tara
AU  - Rawat T
AD  - Division of Medicinal and Process Chemistry, CSIR-Central Drug Research 
      Institute, Lucknow, India.
FAU - Maikhuri, J P
AU  - Maikhuri JP
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Rajender, Singh
AU  - Rajender S
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
FAU - Sharma, V L
AU  - Sharma VL
AD  - Division of Medicinal and Process Chemistry, CSIR-Central Drug Research 
      Institute, Lucknow, India.
FAU - Gupta, Gopal
AU  - Gupta G
AD  - Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India. 
      g_gupta@cdri.res.in.
LA  - eng
PT  - Journal Article
DEP - 20151124
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (DMAP1 protein, human)
RN  - 0 (ESR2 protein, human)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Repressor Proteins)
RN  - TR3MLJ1UAI (Disulfiram)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Disulfiram/*analogs & derivatives
MH  - Enzyme Inhibitors/*administration & dosage/*chemical 
      synthesis/chemistry/pharmacology
MH  - Epigenesis, Genetic/drug effects
MH  - Estrogen Receptor beta/*genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Male
MH  - Mice
MH  - Molecular Docking Simulation
MH  - Promoter Regions, Genetic/drug effects
MH  - Prostatic Neoplasms/*drug therapy/genetics/metabolism
MH  - Repressor Proteins/chemistry/metabolism
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - DNMT1
OT  - cell proliferation
OT  - disulfiram
OT  - estrogen receptor-beta
OT  - prostate cancer
EDAT- 2015/11/26 06:00
MHDA- 2017/05/18 06:00
CRDT- 2015/11/25 06:00
PHST- 2015/08/16 00:00 [received]
PHST- 2015/10/20 00:00 [revised]
PHST- 2015/11/03 00:00 [accepted]
PHST- 2015/11/26 06:00 [pubmed]
PHST- 2017/05/18 06:00 [medline]
PHST- 2015/11/25 06:00 [entrez]
AID - 10.1002/mc.22433 [doi]
PST - ppublish
SO  - Mol Carcinog. 2016 Nov;55(11):1843-1857. doi: 10.1002/mc.22433. Epub 2015 Nov 24.