Repaglinide platinum(IV) conjugates: Enhancing p53 signaling for antitumor and antimetastatic efficacy

Abstract

The tumor suppressor p53 plays multiple roles at the crossroads of suppressing tumor development and metastasis. Here, a series of Repaglinide platinum(IV) conjugates promoting the p53 pathway were designed and prepared, which displayed potent antiproliferative and antimetastatic activities both in vitro and in vivo. Mechanistically, the expression of p53 was upregulated by the synergistic functions of the platinum core through causing severe DNA damage, and the RPG ligand via stimulating the lumican/p53/p21 pathway. The mitochondria-mediated apoptosis was initiated, involving the Bcl-2/Bax/caspase pathway. Pro-death autophagy was initiated with the upregulation of LC3II and down regulation of p62. Additionally, angiogenesis was suppressed by reversing tumor inflammation through the inhibition of key enzymes COX-2, MMP9, and VEGFA. Furthermore, antitumor immunity was enhanced by blocking the immune checkpoint PD-L1, which led to an increased presence of CD3⁺ and CD8⁺ T-cells within the tumor microenvironment.