RT Journal Article
SR Electronic
T1 Dual action of acidic microenvironment on the enrichment of the active metabolite of disulfiram in tumor tissues
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000317
DO 10.1124/dmd.120.000317
A1 Chongzhuang Tang
A1 Xiaoyan Pang
A1 Zitao Guo
A1 Runcong Guo
A1 Lu Liu
A1 Xiaoyan Chen
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/03/23/dmd.120.000317.abstract
AB Disulfiram, an anti-alcoholism drug, could potentially be repurposed as an anticancer drug due to the formation of copper chelate (CuET) from dithiocarb (DTC, a reduced metabolite of disulfiram) and Cu2+. CuET exhibited preferential distribution to tumor tissues. This study investigated the mechanism of CuET accumulation in tumor tissues by employing MDA-MB-231 human breast cancer cells. The concentration of CuET in cells treated with DTC and Cu2+ in acidic culture medium (pH 6.8) was significantly higher than that of the control group (pH 7.4). Subsequently, the effects of pH on the uptake of DTC, Cu2+, and CuET were investigated separately. The acidic environment significantly increased the uptake rate of DTC and Cu2+ but had no effect on CuET. MDA-MB-231 cells overexpressing copper transporter hCTR1 were constructed to evaluate its intermediate role in CuET accumulation. After treatment with CuCl2 followed by DTC for 15 min, the levels of CuET and Cu2+ in hCTR1-overexpressed cells was 2.5-fold higher than that of vector group. In the tumors of cancer xenograft models constructed by hCTR1-MDA-MB-231 cells, the concentrations of CuET and Cu were also significantly higher than those of control group. In conclusion, the acidic microenvironment of tumors can promote the enrichment of CuET in tumors through dual action. On the one hand, it can promote transmembrane transport of DTC by converting ionic DTC into molecular state. On the other hand, it enhances Cu2+ uptake by activating hCTR1, which ultimately leads to the enrichment of CuET. Significance Statement Increasing evidence suggests that the antitumor activity of disulfiram is related to the formation of a copper chelate (CuET) of its reducing metabolite ditiocarb with copper(II) ion, which is preferentially distributed in tumor tissues. We showed that the acidic microenvironment, a common feature of many solid tumor tissues, could promote intracellular CuET accumulation through dual action without changing CuET uptake. This result is helpful for the formulation of clinical dosage regimens of disulfiram in cancer treatment.