Department of Oncology, University of Turin, via Nizza 44, 10126, Turin, Italy.
Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy.
Pharmacol Rep. 2023 Dec;75(6):1588-1596. doi: 10.1007/s43440-023-00531-y. Epub 2023 Oct 5.
Multifunctional thiosemicarbazones (TSCs) able to bind sigma receptors and chelate metals are considered as a promising avenue for the treatment of pancreatic cancer due to the encouraging results obtained on in vitro and in vivo models. Here, we assessed the biochemical mechanism of these TSCs also on lung (A549) and breast (MCF7) cancer cells.
The density of sigma-2 receptors in normal (BEAS-2B and MCF10A) and in lung and breast (A549 and MCF7) cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (by spectrofluorimetric assays to measure Caspases 3/7/9; qRT-PCR detection of GRP78, ATF6, IRE1, PERK; MitoSOX, DCFDA-AM and JC-1 staining), induced by the TSCs FA4, MLP44, PS3 and ACThio1, were evaluated.
FA4 and PS3 exerted more potent cytotoxicity than MLP44 and ACThio1 in all cancer cell lines, where the density of sigma-2 receptors was higher than in normal cells. Remarkably, FA4 promoted ER- and mitochondria-dependent cell death pathways in both cell models, whereas the other TSCs had variable, cell-dependent effects on the activation of the two proapoptotic pathways.
Our data suggest that FA4 is a promising compound that deserves to be further studied for lung and breast cancer treatment. However, the other multifunctional TSCs also hold promise for the development of therapies towards a personalized medicine approach. Indeed, the presence of the sigma-2 receptor-targeting moiety would lead to a more specific tumor delivery embracing the characteristics of individual tumor types.
多功能硫代缩氨基脲（TSCs）能够结合sigma 受体并螯合金属，由于在体外和体内模型中获得的令人鼓舞的结果，被认为是治疗胰腺癌的有前途的途径。在这里，我们还评估了这些 TSCs 在肺（A549）和乳腺（MCF7）癌细胞中的生化机制。
通过流式细胞术评估正常（BEAS-2B 和 MCF10A）和肺和乳腺（A549 和 MCF7）癌细胞中 sigma-2 受体的密度。在这些细胞中，通过 MTT 测定评估 TSCs FA4、MLP44、PS3 和 ACThio1 诱导的细胞毒性（MTT 测定）和 ER 和线粒体依赖性细胞死亡途径的激活（通过荧光光度法测定 Caspases 3/7/9；qRT-PCR 检测 GRP78、ATF6、IRE1、PERK；MitoSOX、DCFDA-AM 和 JC-1 染色）。
FA4 和 PS3 在所有癌细胞系中的细胞毒性均强于 MLP44 和 ACThio1，而 sigma-2 受体的密度高于正常细胞。值得注意的是，FA4 促进了两种细胞模型中的 ER 和线粒体依赖性细胞死亡途径，而其他 TSCs 对两种促凋亡途径的激活具有不同的、细胞依赖性的影响。
我们的数据表明，FA4 是一种很有前途的化合物，值得进一步研究用于治疗肺癌和乳腺癌。然而，其他多功能 TSCs 也为开发针对个性化医疗方法的治疗方法提供了希望。事实上，sigma-2 受体靶向部分的存在将导致更具特异性的肿瘤输送，包括个体肿瘤类型的特征。
