A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts

• Published in: Toxicology and applied pharmacology 2013-12, Vol.273 (3), p.477-483
• Main Authors: Han, Jinbin, Liu, Luming, Yue, Xiaoqiang, Chang, Jinjia, Shi, Weidong, Hua, Yongqiang
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - pharmacology; APOPTOSIS; Apoptosis - drug effects; Biological and medical sciences; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Cell Line, Tumor; CELL PROLIFERATION; Cell Proliferation - drug effects; COPPER; Copper - pharmacology; Copper(I); Diethyldithiocarbamate; Disease Models, Animal; Disulfiram - pharmacology; Ditiocarb - pharmacology; DRUGS; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; In Situ Nick-End Labeling; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; MICE; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NEOPLASMS; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; PANCREAS; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; PROTEINS; Toxicology; Tumors; WATER; Xenograft Model Antitumor Assays
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.09.009

It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. •A new structure of DDTC–Cu(I) was reported for the first time.•DDTC–Cu(I) dissolved directly in water was for in vitro and in vivo uses.•DDTC–Cu(I) demonstrated significant anticancer effect in vitro and in vivo.•DDTC–Cu(I) is capable of inhibiting proteasome activity in vitro and in vivo.