Atypical teratoid/rhabdoid tumor (AT/RT) is the most malignant tumor of the central nervous system that generally occurs in young children. Despite the use of intensive multimodal therapy for AT/RT, the prognosis is still poor. The brain tumor initiating cells in AT/RT cells has been suggested as one of the challenges in AT/RT treatment. These cells have high expression of aldehyde dehydrogenase (ALDH). We investigated the combination effect of the ALDH inhibitor, disulfiram and cisplatin in the treatment of AT/RT cells. Isobologram analysis revealed that the combination therapy synergistically increases AT/RT cell death. The enzyme activity of ALDH AT/RT cells was effectively reduced by the combination therapy. We proposed that the synergistic augmentation occurs, at least partially through an increase in cleaved Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis mediated by activating transcription factor 3 (ATF3). In AT/RT mouse model, the combination therapy decreased tumor volume and prolonged the survival. Immunofluorescence assay in mouse brain tissues were consistent with expression of ATF3 and cleaved PARP. Our study demonstrates enhanced anti-cancer effect of combination therapy of disulfiram and cisplatin. This combination might provide a viable therapeutic strategy for AT/RT patients.

中文翻译：

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双硫仑可增强顺铂在非典型类畸形/类胡萝卜素肿瘤（AT / RT）中的抗癌作用。

非典型的类畸胎/类胡萝卜瘤（AT / RT）是中枢神经系统最恶性的肿瘤，通常发生在幼儿中。尽管对AT / RT使用了强化的多峰疗法，但预后仍然很差。已经提出AT / RT细胞中的脑肿瘤起始细胞是AT / RT治疗中的挑战之一。这些细胞具有高表达的醛脱氢酶（ALDH）。我们研究了ALDH抑制剂，双硫仑和顺铂在AT / RT细胞治疗中的联合作用。等效线图分析表明，联合治疗协同增加了AT / RT细胞死亡。联合治疗有效降低了ALDH AT / RT细胞的酶活性。我们提出发生协同增效，至少部分地通过激活转录因子3（ATF3）介导的裂解的聚（ADP-核糖）聚合酶（PARP）依赖性细胞凋亡的增加来实现。在AT / RT小鼠模型中，联合治疗可减少肿瘤体积并延长生存期。小鼠脑组织中的免疫荧光测定与ATF3的表达和裂解的PARP一致。我们的研究证明了双硫仑和顺铂联合治疗的抗癌作用增强。这种组合可能为AT / RT患者提供可行的治疗策略。我们的研究证明了双硫仑和顺铂联合治疗的抗癌作用增强。这种组合可能为AT / RT患者提供可行的治疗策略。我们的研究证明了双硫仑和顺铂联合治疗的抗癌作用增强。这种组合可能为AT / RT患者提供可行的治疗策略。