An atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive tumor of the central nervous system that generally occurs in children under three years of age. There is no effective chemotherapy in most AT/RT patients. Within a tumor, small subpopulation cells called cancer stem cells do not respond to or are resistant to conventional anticancer drugs. In previous our studies, we observed the expression of aldehyde dehydrogenase (ALDH), a stem cell marker in AT/RT cells. Based on this, we confirmed the anticancer effect using disulfiram (DSF) known as ALDH inhibitor. Herein, we have investigated the anticancer effect of DSF with cisplatin in order to improve the effectiveness of AT/RT treatment.
Patient-derived primary cultured cells and established cell lines were utilized in vitro experiments. The combination effects of DSF with cisplatin was confirmed by cell viability, flow cytometry, ELISA and immunofluorescence analysis. The mechanism was identified by western blot analysis. Tumor volumes and survival rates were analyzed via bioluminescence live imaging in an AT/RT orthotopic xenograft mouse model to verify in vivo therapeutic effects.
Our results demonstrate the anticancer effects of the combination of DSF and cisplatin both in vitro and in vivo. The combined treatment significantly inhibited the cell viability and ALDH enzyme activity of all AT/RT cells. The combination of DSF and cisplatin has been shown to modulate C-jun and ATF3 protein expression and activate PARP to induce apoptosis much more effectively. Importantly, the combination of DSF with cisplatin resulted in decreased tumor volume and increased long-term survival rate in AT/RT animal models.
Our study suggests that combination therapy of DSF and cisplatin can be used as a novel treatment strategy for AT/RT, which is difficult to treat with conventional chemotherapy.
The authors.
Grant from the Seoul National University Hospital Research Fund (04-2018-0280) and a grant from the National Research Foundation (NRF) of Korea (2017R1A2B2008422).
All authors have declared no conflicts of interest.