Targeting cancer stem cells by disulfiram and copper sensitizes radioresistant chondrosarcoma to radiation.
Targeting cancer stem cells by disulfiram and copper sensitizes radioresistant chondrosarcoma to radiation.
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DOI：
10.1016/j.canlet.2021.02.002
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发表时间：
2021-05-01
期刊：
影响因子：
9.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wang K;Michelakos T;Wang B;Shang Z;DeLeo AB;Duan Z;Hornicek FJ;Schwab JH;Wang X
软骨肉瘤（CS）是第二常见的原发性骨肿瘤，需要克服其放射敏感性。在许多恶性肿瘤中，放射抗性归因于癌症干细胞（CSC）。双硫仑（DSF）是一种经FDA批准的抗酒精中毒药物，与铜络合（DSF/Cu）可使上皮CSCs放射增敏。这促使我们研究DSF/Cu对CS CSC（CCSCs）的放射增敏作用。采用体外细胞系SW 1353和CS-1研究DSF/Cu对CCSCs的放射增敏作用。通过CCSC（ALDH+ CD 133+）的流式细胞术、球体形成能力和干性基因蛋白表达的Western印迹分析独立地鉴定干性。通过分析异种移植物生长和残留异种移植物的干性，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。CCSCs对单次剂量照射（IR）和分次照射（FIR）具有抗性。IR和FIR增加了CS的干性。IR和FIR与DSF/Cu联用，可消除CS干性。RT + DSF/Cu在抑制原位CS异种移植物生长方面比RT ± DSF更安全和有效。总之，DSF/Cu使CCSC放射增敏。这些结果可以转化为临床试验的CS患者需要RT改善的结果。
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.
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