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Abstract：
The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ2) receptor was recently proposed as a promising target for pancreatic cancer therapy, we explored our previously developed multifunctional thiosemicarbazones, designed to synergistically impair cell energy levels, by targeting σ2 and P-gp proteins and chelating Iron. A deconstruction approach was herein applied by removing one function at a time from the potent multifunctional thiosemicarbazones 1 and 2, to investigate the contribution to cytotoxicity of each target involved. The results from in vitro (panel of pancreatic tumor cells) and in vivo experiments (C57BL/6 bearing KP02 tumor), suggest that while the multifunctional activity was not required for the antitumor activity of these thiosemicarbazones, σ2-targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of σ2-targeting.
摘要：
胰腺癌的侵袭性迫切需要更有效的治疗选择。由于sigma-2（σ2）受体最近被提出作为胰腺癌治疗的有希望的靶标，我们探索了我们以前开发的多功能缩氨基硫脲，旨在协同损害细胞能量水平，通过靶向σ2和P-gp蛋白和螯合铁。本文应用解构方法,通过一次从有效的多功能缩氨基硫脲1和2中去除一个功能,以研究对所涉及的每个靶标的细胞毒性的贡献。来自体外（胰腺肿瘤细胞组）和体内实验（携带KP02肿瘤的C57BL/6）的结果，这表明，虽然这些氨基硫脲的抗肿瘤活性不需要多功能活性，σ2靶向似乎允许替代肿瘤细胞死亡机制，与其他缺乏σ2靶向的硫代氨基脲相比，导致有效且毒性较小的脱靶毒性。
