Trabectedin 被批准用于治疗软组织肉瘤 (STS)，它会干扰细胞分裂和基因转录过程。由于其仅在某些组织型中具有很强的抗肿瘤活性，目前正在进行一些关于曲贝替定组合的研究以提高其疗效。在这项研究中，我们旨在研究新的潜在治疗策略，通过综合计算机、体外和体内方法来增强曲贝替定的抗肿瘤作用。对于计算机分析，我们筛选了两个公共数据集：GSEA M5190 和 TCGA SARC。纤维肉瘤、平滑肌肉瘤、去分化和粘液样脂肪肉瘤细胞系用于体外研究。对于体内实验，开发了纤维肉瘤原位小鼠模型。计算机分析确定 Glo1 是曲贝替定治疗后唯一上调的药物靶标，并且与不良预后相关。特异性 Glo1 抑制剂 S-p-溴苄基谷胱甘肽环戊基二酯 (BBGC) 增加了曲贝替定在 STS 细胞中的细胞毒性，并恢复了对曲贝替定耐药的粘液样脂肪肉瘤细胞的药物敏感性。此外，BBGC和曲贝替定联合治疗在体内具有协同抗肿瘤作用，且对小鼠没有任何额外的毒性。基于这些结果，我们认为 BBGC 值得进一步研究，以评估其与 Trabectedin 联合使用的潜在临床用途。© 2024。作者。

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin.© 2024. The Author(s).