MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, P. R. China.
Department of Surgery, P.O.F. Hospital, Wah Cantt 47040, Pakistan.
Inorg Chem. 2020 Sep 8;59(17):12632-12642. doi: 10.1021/acs.inorgchem.0c01736. Epub 2020 Aug 24.
Multifunctional platinum anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinum anticancer agents. Herein, we develop dual and triple action platinum complexes with targeted and biological active functionalities. One complex () that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that mainly accumulates in mitochondria. As a result, disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from . Furthermore, treatment with impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.
多功能铂类抗癌前药有可能丰富抗癌特性，并克服铂类抗癌药物的耐药性和副作用等临床问题。在此，我们开发了具有靶向和生物活性功能的双重和三重作用的铂配合物。一个配合物 () 由顺铂、替加氟和氨鲁米特组成，对三阴性乳腺癌 (TNBC) 细胞表现出很强的细胞毒性。细胞摄取和分布研究表明， 主要积聚在线粒体中。结果， 破坏了线粒体的超微结构，并导致线粒体膜电位发生显著变化，这进一步导致活性氧 (ROS) 的产生增加和 MDA-MB-231 TNBC 中 ATP 合成的减少。Western blot 分析显示胸苷酸合成酶的三元复合物的形成，这表明替加氟从 中释放后在细胞内转化为 5-FU。此外， 处理会损害线粒体功能，通过线粒体途径抑制糖酵解和线粒体呼吸，并诱导细胞凋亡。RNA 测序实验表明， 可以扰乱涉及 DNA 合成、DNA 损伤、代谢和转录活性的途径。这些发现表明 可以干预包括 DNA 损伤、胸苷酸合成酶抑制和线粒体生物能量学干扰在内的多个细胞过程，以杀死癌细胞。这些结果强调了三重作用前药在三阴性乳腺癌高效抗癌治疗中的重要性。
