Targeting cancer stem cells by disulfiram and copper sensitizes radioresistant chondrosarcoma to radiation.

ABSTRACT: Overcoming the radiosensitivity of chondrosarcoma (CS), the second most common primary bone tumor, is needed. Radioresistance is attributed to cancer stem cells (CSCs) in many malignancies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, complexed with Cu (DSF/Cu) can radiosensitize epithelial CSCs. This prompted us to investigate the radiosensitizing effect of DSF/Cu on CS CSCs (CCSCs). The radiosensitizing effects of DSF/Cu on CCSCs were investigated in vitro using cell lines SW1353 and CS-1. Stemness was identified independently by flow cytometry for CCSCs (ALDH⁺CD133⁺), sphere-forming ability, and Western blot analysis of stemness gene protein expression. The radiosensitizing effect of DSF/Cu was studied in an orthotopic CS xenograft mouse model by analyzing xenograft growth and residual xenografts for stemness. CCSCs were found to be resistant to single-dose (IR) and fractionated irradiation (FIR). IR and FIR increased CS stemness. Combined with DSF/Cu in vitro and in vivo, IR and FIR eliminated CS stemness. RT + DSF/Cu was safer and more effective than either RT ± DSF in inhibiting growth of orthotopic CS xenografts. In conclusion, DSF/Cu radiosensitizes CCSCs. These results can be translated into clinical trials for CS patients requiring RT for improved outcomes.

SUBMITTER: Wang K 

PROVIDER: S-EPMC8969896 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature