Rácz Bálint, Kincses Annamária, Laczi Krisztián, Rákhely Gábor, Domínguez-Álvarez Enrique, Spengler Gabriella
Department of Medical Microbiology, Albert Szent-Györgyi Health Center and Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary.
Department of Biotechnology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, 6726 Szeged, Hungary.
Pharmaceutics. 2023 Feb 11;15(2):610. doi: 10.3390/pharmaceutics15020610.
Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the ABCB1 protein. The combined effect of the compounds with doxorubicin was demonstrated with a checkerboard assay. The ABCB1 inhibitory and the apoptosis-inducing effects of the derivatives were measured with flow cytometry. Whole transcriptome sequencing was carried out on Illumina platform upon the treatment of resistant cells with the most potent derivatives. One ketone and three methyl ester selenoesters showed synergistic or weak synergistic interaction with doxorubicin, respectively. Ketone selenoesters were the most potent ABCB1 inhibitors and apoptosis inducers. Nitrile selenoesters could induce moderate early and late apoptotic processes that could be explained by their ABCB1 modulating properties. The transcriptome analysis revealed that symmetrical selenoesters may influence the redox state of the cells and interfere with metastasis formation. It can be assumed that these symmetrical selenocompounds possess toxic, DNA-damaging effects due to the presence of two selenium atoms in the molecule, which may be augmented by the presence of symmetrical groups.
最近，含硒衍生物在药物化学领域引起了更多关注。在本研究中，通过研究表达ABCB1蛋白的敏感和耐药人结肠腺癌细胞中流出泵相关耐药性的逆转以及凋亡抗性，对对称硒酯的抗癌活性进行了研究。采用棋盘法证明了这些化合物与阿霉素的联合作用。通过流式细胞术测定了衍生物的ABCB1抑制作用和凋亡诱导作用。在用最有效的衍生物处理耐药细胞后，在Illumina平台上进行了全转录组测序。一种酮硒酯和三种甲酯硒酯分别与阿霉素表现出协同或弱协同相互作用。酮硒酯是最有效的ABCB1抑制剂和凋亡诱导剂。腈硒酯可诱导中度的早期和晚期凋亡过程，这可以用它们对ABCB1的调节特性来解释。转录组分析表明，对称硒酯可能影响细胞的氧化还原状态并干扰转移形成。可以推测，由于分子中存在两个硒原子，这些对称硒化合物具有毒性和DNA损伤作用，对称基团的存在可能会增强这种作用。
