Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

Abstract

Metastasis is the major obstacle to the survival of cancer patients. Herein, a series of new desloratadine platinum(IV) conjugates with promising antiproliferative and antimetastatic activities were developed and evaluated. The candidate complex caused significant DNA damage and stimulated mitochondrial apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it suppressed the epithelial–mesenchymal transition (EMT) process in tumors effectively through NMT-1/HPCAL1 and β-catenin signaling. Subsequently, the angiogenesis was inhibited with the downregulation of key proteins HIF-1α, VEGFA, MMP-9, and CD34. Moreover, the antitumor immunity was effectively aroused by the synergism of EMT reversion and decrease of the histamine level; then, the macrophage polarization from M2- to M1-type and the increase of CD4+ and CD8+ T cells were triggered simultaneously in tumors.

Canadine Platinum(IV) Complexes Targeting Epithelial–Mesenchymal Transition as Antiproliferative and Antimetastatic Agents

“…In view of these stimulating facts and as a continuation of our interest in developing novel antitumor agents, − it was of great interest for us to design novel platinum(IV) conjugates with EMT suppressing and immunoregulating properties. Isoquinoline alkaloids are an important group of natural bioactive products, which display a wide variety of pharmacological properties such as antimicrobial, antibacterial, antifungal, antitumor, etc. − Canadine (CND) as a unique isoquinoline alkaloid shows much potential as antiproliferative and antimetastasis agents. − The mechanism detection revealed that CND was potent in inhibiting the EMT process, , inhibiting inflammation, and further modulating immune responses. , Accordingly, we intended to incorporate CND into the platinum(IV) system as a functional ligand with the aim of discovering novel platinum(IV) agents with potent antiproliferative and antimetastatic properties.…”