Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response
Ming Zhang, Yan Chen, Zhifang Liu, Min Liu, Qingpeng Wang
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.