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.

Background: PML-RARα oncoprotein is a fusion protein in more than 95% of patients with acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) is an efficacious therapeutic agent for the treatment of acute promyelocytic leukemia (APL), and the mechanism involves the binding with PML and degradation of PML-RARα protein. Pyrrolidine dithiocarbamate (PDTC) demonstrates the function of facilitating the cytotoxic effect of ATO. Purpose: To investigate whether PDTC is potential to enhance the cytotoxic effect of ATO to APL cells by acting on PML-RARα oncoproteins. Methods: Inhibitory effects of drugs on cell viability were examined by CCK-8 test, and apoptosis was evaluated by flow cytometry. Western blotting and immunofluorescence assays were used to explore the mechanism. Results: PDTC improved the effect of ATO on inhibiting proliferation of NB4 cells in vitro. Further, PDTC-ATO promoted apoptosis and cell cycle arrest in NB4 cells. The expression of caspase-3 and Bcl-2 was reduced in PDTC-ATO-treated NB4 cells, while cleaved caspase-3 and Bax was up-regulated. Furthermore, less PML-RARα expression were found in PDTC-ATO-treated NB4 cells than that in NB4 cells treated with ATO singly. Laser confocal microscopy showed that protein colocalization of PML and RARα was disrupted more significantly by PDTC-ATO treatment than that with ATO monotherapy. Conclusions: In conclusion, PDTC enhances the cytotoxic effect of ATO on APL, and the mechanism is, at least in part, related to the promotion of ATO-induced degradation of PML-RARα fusion protein via forming a complex PDTC-ATO.

Objective: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. Methods: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. Results: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) ( P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. Conclusion: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.