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 in vitro
and in vivo. It induces serious DNA damage and further leads to high
expression of γ-H2AX and p53. Moreover, it promotes apoptosis
of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3.
Then, COX-2, MMP-9, NLRP3, and caspase1 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+ T infiltrating cells
in tumor tissues.