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

Cancer Lett. 2021 May 1;505:37-48. doi: 10.1016/j.canlet.2021.02.002. Epub 2021 Feb 11.

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.

Keywords: CCSCs; NF-κB; Radioresistance; Radiosensitizing; Stemness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / analysis
  • Aldehyde Dehydrogenase / analysis
  • Animals
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology
  • Bone Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Chondrosarcoma / mortality
  • Chondrosarcoma / pathology
  • Chondrosarcoma / radiotherapy*
  • Copper / pharmacology*
  • Disulfiram / pharmacology*
  • Dose Fractionation, Radiation
  • Female
  • Humans
  • Mice
  • Neoplastic Stem Cells / drug effects*
  • Radiation-Sensitizing Agents / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • AC133 Antigen
  • Radiation-Sensitizing Agents
  • Copper
  • Aldehyde Dehydrogenase
  • Disulfiram