Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs). FA4 has shown potent activity against pancreatic cancer in vivo. We synthesized complexes of FA4 with Cu(II) and Pt(II), and compared their efficacy with complexes of the non-S2R-targeting TSC 1. TSC-Cu exhibited over 50-fold higher in vitro cytotoxicity than TSCs-Pt, which was less active than TSCs. FA4-Cu induced apoptotic cell death via ER and mitochondrial stress showing more potent activity than FA4. This in vitro effect was replicated in the preclinical PANC-1 model, where FA4-Cu was more potent than FA4, 1, and 1-Cu. These results support further exploration of FA4-Cu as a potential therapy for pancreatic cancer.

中文翻译：

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靶向 Sigma-2 受体 （S2R） 的同类首创硫代氨基甲酮金属配合物作为胰腺癌的创新策略


胰腺癌的发病率不断上升，5 年生存率最低，预计到 2030 年将成为癌症死亡的第二大原因。目前的临床试验显示改善有限，凸显了对新疗法的需求。sigma-2 受体 （S2R） 在肿瘤进展中发挥作用，是新型硫代氨基甲酸钠 （TSC） 的靶点。FA4 在体内显示出对胰腺癌的有效活性。我们合成了 FA4 与 Cu（II） 和 Pt（II） 的复合物，并将其与非 S2R 靶向 TSC 1 的复合物的功效进行了比较。TSC-Cu 的体外细胞毒性比 TSCs-Pt 高 50 倍以上，而 TSCs-Pt 的活性低于 TSCs。FA4-Cu 通过 ER 诱导凋亡细胞死亡，线粒体应激显示出比 FA4 更有效的活性。这种体外效应在临床前 PANC-1 模型中复制，其中 FA4-Cu 比 FA4、1 和 1-Cu 更有效。这些结果支持进一步探索 FA4-Cu 作为胰腺癌的潜在疗法。