Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma

Abstract

(64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is an imaging agent for positron emission tomography (PET) that targets hypoxic tumors. (64)Cu-ATSM is also reported to be a potential agent for internal radiotherapy. In a mouse colon carcinoma (Colon-26) model, we have shown that (64)Cu-ATSM preferentially localizes in intratumoral regions with a high density of CD133(+) cells, which show characteristics of cancer stem cells or cancer stem cell-like cells (collectively referred here as CSCs). In this study, we evaluated the therapeutic effect of (64)Cu-ATSM in relation to CD133 expression using this model. Systemic administration of 37 MBq (64)Cu-ATSM or saline was conducted twice within a 1-week interval to mice bearing 1-week-old Colon-26 tumors (days 0-7). At day 19, tumor size measurement, flow cytometry analysis and experimental lung metastatic assay were performed. The therapeutic effect of (64)Cu-ATSM on sorted CD133(+) and CD133(-) Colon-26 cells was also examined in vitro. In vivo studies showed that (64)Cu-ATSM treatment inhibited tumor growth. The percentage of CD133(+) cells and metastatic ability in (64)Cu-ATSM treated tumors was decreased compared with that in control animals. In vitro studies demonstrated that (64)Cu-ATSM accumulated in cells under hypoxic conditions and incorporation of (64)Cu-ATSM under hypoxia caused cell death in both CD133(+) and CD133(-) cells in a similar extent. (64)Cu-ATSM administration reduced tumor volume as well as the percentage of CD133(+) cells and the metastatic ability of Colon-26 tumors. Together with our data, it is suggested that (64)Cu-ATSM accumulates in regions high in CD133(+) highly tumorigenic cells and kills such regions by radiation, resulting in a decrease of the percentage of CD133(+) cells.