Development of a series of flurbiprofen and zaltoprofen platinum(IV) complexes with anti-metastasis competence targeting COX-2, PD-L1 and DNA.

Abstract

To develop new anti-metastasis chemotherapeutic drugs, a series of flurbiprofen (FLP) and zaltoprofen (ZTP) platinum(IV) complexes targeting COX-2, PD-L1 and DNA was prepared and investigated. Complex 2 with dual FLP ligands displays promising antitumor activities in vitro and exhibits much potential in overcoming drug resistance. More importantly, the antitumor evaluation in vivo demonstrates that complex 2 possesses promising inhibition of cancer growth and metastasis simultaneously. Further investigation of the mechanism revealed the multi-specific antitumor function of complex 2. It exerts remarkable DNA damage after reduction to platinum(II) complex, and up-regulates the expression of p53 and γ-H2AX. Then, complex 2 promotes mitochondria-mediated apoptosis effectively by activating the Bcl-2/Bax/caspase3 pathway. Furthermore, inflammation in tumor tissues is restrained by the suppression of enzymes COX-2, MMP-9, NLRP3 and caspase1, which would favor the inhibition of tumor metastasis. Moreover, compound 2 boosts T-cell immunity by restraining PD-L1 expression, and further improving the density of CD3+ and CD8+ T cells in tumor tissues.