Dual Mitochondria‐ and DNA‐Targeting Coumarin‐Pt(IV) Prodrug for the Enhancement of Anticancer Performance. Issue 19 (14th June 2022)

• Record Type: Journal Article
• Authors: Tu, Ying; Li, Hao‐Ming; Wang, Meng‐Meng; Su, Yan; Liu, Hong‐Ke; Su, Zhi
• Is Part Of: European journal of inorganic chemistry. Volume 2022:Issue 19(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-14
• Subjects: Anticancer agents -- Apoptosis -- DNA-targeting -- Mitochondria-targeting -- Platinum -- Prodrugs; Chemistry, Inorganic -- Periodicals; Organometallic chemistry -- Periodicals; Bioinorganic chemistry -- Periodicals; Solid state chemistry -- Periodicals; 546
• DOI: 10.1002/ejic.202200184
• Languages: English
• ISSNs: 1434-1948

Abstract

Abstract: Cisplatin (CDDP) was considered as the milestone anticancer agent for the cancer treatment, however, the side effects were also a huge threat to human health. Pt(IV) prodrug with functional axial decoration has been demonstrated to be an effective strategy to minor the side effect. In this work, we have developed a dual mitochondrial and DNA‐targeting Pt(IV) prodrug with coumarin‐derivative decoration, and the experiment has illustrated that the prodrug Pt‐CMN could dramatically enhance the anticancer performance compared to CDDP. Prodrug Pt‐CMN could be activated in vitro by reducing reagent ascorbic acid in the periods of 6 h. Control prodrug Pt‐CM without the diethylamino group, showed much less cytotoxicity to cancer cells, which partially resulted from the hard reduction of prodrug Pt‐CM . Furthermore, prodrug Pt‐CMN could increase the Pt cellular uptake in MCF‐7 cells and destroy the functionality of mitochondria, including inducing the ROS generation, losing the mitochondrial membrane potential (MMP), and decreasing the ATP production. Moreover, prodrug Pt‐CMN could induce the intracellular DNA damage of MCF‐7 cells to activate apoptosis and arrest the cell cycle in the G2/M phase. This work not only demonstrated that prodrug Pt‐CMN could be a promising anticancer agent, but also provided a new strategy to enhance the anticancer performance through the subcellular organelle targeting. Abstract : A dual mitochondria‐ and DNA‐targeting coumarin‐Pt(IV) prodrug has been developed, which dramatically enhances the anticancer performance and has reduced side‐effects compared to cisplatin. Prodrug Pt‐CMN induces the dysfunctionality of mitochondria and the intracellular DNA damage of MCF‐7 cells, activates the apoptosis, and arrests the cell cycle in the G2/M phase.