Combination of Disulfiram and Copper-Cysteamine Nanoparticles for an Enhanced Antitumor Effect on Esophageal Cancer

Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide with a low 5 year survival rate. More effective chemotherapeutic drugs, either new or repurposing ones, are urgently needed. Disulfiram (DSF) is a safe and public domain drug for alcohol addiction treatment and later shown to have anticancer capability, especially when administrated together with copper. The present study is to test the hypothesis that developed copper-cysteamine (Cu-Cy) nanoparticles (NPs) can enhance the antitumor effect of DSF on esophageal cancer with a reduced risk of copper poisoning. Our results showed that Cu-Cy NPs could greatly facilitate DSF to inhibit cell proliferation in cultured human esophageal cancer cells. Interestingly, the combined inhibitory function could be further enhanced when DSF and Cu-Cy NPs were present at an optimal molar ratio of 1:4. The results of the change in physical color, UV-vis absorption and fluorescence spectra, X-ray diffraction patterns, and FTIR spectra from a mixture of DSF and Cu-Cy NPs suggest a possible reaction between DSF and Cu-Cy NPs and the formation of a complex. Furthermore, cellular mechanistic studies revealed that the combination of DSF and Cu-Cy NPs resulted in reactive oxygen species accumulation and blocked nuclear translocation of NF-κB (p65) in esophageal cancer cells. Moreover, in xenograft nude mice, combined administration of DSF and Cu-Cy NPs greatly inhibited tumor growth without noticeable histological toxicity, while any single agent at the same doses presented no inhibitory function. Together, this study demonstrates an effective anticancer function of combined treatment of DSF and Cu-Cy NPs in vitro and in vivo, which could be a promising chemotherapy for esophageal cancer patients.