Ketoprofen and Loxoprofen Platinum(IV) Complexes Displaying Antimetastatic Activities by Inducing DNA Damage, Inflammation Suppression, and Enhanced Immune Response

Metastasis is a major contributor of death in cancer patients, and there is an urgent need for effective treatments of metastatic malignancies. Herein, ketoprofen (KP) and loxoprofen (LP) platinum(IV) complexes with antiproliferative and antimetastatic properties were designed and prepared by integrating chemotherapy and immunotherapy targeting cyclooxygenase-2(COX-2), matrix metalloproteinase-9 (MMP-9), and programmed death ligand 1 (PD-L1), besides DNA. A mono-KP platinum(IV)complex with a cisplatin core is screened out as a candidate possessing potent anti-proliferative and anti-metastasis activities both invitro and in vivo. It induces serious DNA damage and further leads to high expression of gamma-H2AX and p53. Moreover, it promotes apoptosis of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3. Then, COX-2, MMP-9, NLRP3, andcaspase1 as pivotal enzymes igniting inflammation and metastasis are obviously inhibited. Notably, it significantly improves immune response through restraining the expression of PD-L1 to increase CD3+and CD8+Tinfiltrating cells in tumor tissues

Automated summary

The study developed a ketoprofen platinum(IV) complex with potent anti-proliferative and anti-metastasis activities by inducing DNA damage and promoting apoptosis of tumor cells, thus inhibiting inflammation and metastasis.