Targeting cancer stem cells by disulfiram and copper sensitizes radioresistant chondrosarcoma to radiation. (1st May 2021)

• Record Type: Journal Article
• Authors: Wang, Kun; Michelakos, Theodoros; Wang, Bing; Shang, Zikun; DeLeo, Albert B.; Duan, Zhenfeng; Hornicek, Francis J.; Schwab, Joseph H.; Wang, Xinhui
• Is Part Of: Cancer letters. Volume 505(2021)
• Page Start: 37
• Page End: 48
• Publication Date: 2021-05-01
• Subjects: Stemness -- NF-κB -- CCSCs -- Radioresistance -- Radiosensitizing; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.02.002
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Overcoming radioresistance in chondrosarcoma (CS) is an unmet clinical need. Chondrosarcoma stem cells (CCSCs) are radioresistant and induced by radiation. Disulfiram combined with copper (DSF/Cu) radiosensitizes CCSCs in vitro and in vivo . DSF/Cu expands the therapeutic index of radiation in an orthotopic CS mouse model. The first example of mesenchymal originated CSCs radiosensitized by DSF/Cu.