Determine the Anticancer Activity and Mechanism of Overcoming Drug Resistance by Cu(DDC)2 NPs in Prostate Cancers

Abstract

Copper diethyldithiocarbamate [Cu(DDC)2] complex formed by disulfiram (DSF) and copper ions is a promising therapeutic agent for cancer treatment. However, the poor aqueous solubility of Cu(DDC)2 limited its clinical application. In our previous studies, we developed a stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)2 nanoparticle (NP) as an injectable formulation with high drug concentration and excellent physicochemical properties. Our initial in vitro studies also demonstrated its potent anticancer activities. In the current study, we extensively investigated the in vitro anticancer activities of Cu(DDC)2 NP and demonstrated that it could kill drug-resistant prostate cancer cells by inducing non-apoptotic cell death. Further, Cu(DDC)2 NP effectively inhibited the tumor growth in an in vivo paclitaxel-resistant tumor model. In addition, we also performed studies to explore the mechanism of overcoming drug resistance by Cu(DDC)2 NP. Our results showed that Cu(DDC)2 NP did not affect the P-gp activity or change the level of P-gp proteins. It overcomes drug resistance because it is not a substrate of P-gp. Therefore, the use of Cu(DDC)2 NP will not affect the normal function of P-gp and avoid the toxic side effects associated with P-gp inhibitors. It will be a promising therapeutic agent for treating drug-resistant prostate cancers or other solid tumors.