Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA; Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Cancer Lett. 2021 May 1;505:37-48. doi: 10.1016/j.canlet.2021.02.002. Epub 2021 Feb 11.
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 (ALDHCD133), 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.
克服软骨肉瘤（CS）的放射敏感性是必要的。CS 是第二大常见的原发性骨肿瘤，放射抵抗归因于许多恶性肿瘤中的癌症干细胞（CSC）。双硫仑（DSF），一种 FDA 批准的抗酒精中毒药物，与 Cu 络合（DSF/Cu）可以增敏上皮 CSC。这促使我们研究 DSF/Cu 对 CS CSC（CCSC）的放射增敏作用。我们通过体外使用 SW1353 和 CS-1 细胞系研究了 DSF/Cu 对 CCSC 的放射增敏作用。通过流式细胞术对 CCSC（ALDHCD133）、球体形成能力和干性基因蛋白表达的 Western blot 分析，独立鉴定干性。通过分析异种移植生长和残留异种移植中的干性，在原位 CS 异种移植小鼠模型中研究了 DSF/Cu 的放射增敏作用。发现 CCSC 对单次剂量（IR）和分次照射（FIR）均有抗性。IR 和 FIR 增加了 CS 的干性。体外和体内联合使用 DSF/Cu，IR 和 FIR 消除了 CS 的干性。RT+DSF/Cu 比 RT±DSF 更安全、更有效地抑制原位 CS 异种移植的生长。总之，DSF/Cu 增敏 CCSC。这些结果可以转化为需要 RT 的 CS 患者的临床试验，以提高治疗效果。
