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]

• Published in: Molecular carcinogenesis 2016-11, Vol.55 (11), p.1843-1857
• Main Authors: Sharma, Vikas, Verma, Vikas, Lal, Nand, Yadav, Santosh K, Sarkar, Saumya, Mandalapu, Dhanaraju, Porwal, Konica, Rawat, Tara, Maikhuri, JP, Rajender, Singh, Sharma, VL, Gupta, Gopal
• Format: Article
• Language: English
• Subjects: Cancer therapies; Epigenetics; Gene therapy; Pharmacology; Prostate cancer
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22433

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. © 2015 Wiley Periodicals, Inc.