Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

Abstract

Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes.Cyclooxygenase-2 (COX-2) playsavital role in the progression of BC,c orrelating with the expression of programmed death-ligand 1(PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells,a nd its blockade would stimulate anticancer immunity.T wo multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells.D NP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX;m oreover,i td isplayed potent antitumor activity and almost no general toxicity in mice bearing triplenegative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo,inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells.T hese findings demonstrate that DNP is capable of intervening in inflammatory,i mmune,a nd metastatic processes of BC,t hus presenting anew mechanism of action for anticancer platinum-(IV) complexes.T he multispecificity offers as pecial superiority for DNP to treat TNBC by combining chemotherapyand immunotherapyi none molecule.

Pt(IV) Prodrugs with NSAIDs as Axial Ligands

“…For prodrug 21 , IC 50 values varied from 0.34 to 0.17 µM, which is up to 187-fold more than that of cisplatin, while prodrug 10 showed IC 50 values from 1.11 to 0.4 µM. It is worth noting that the IC 50 values obtained by Jin et al for prodrug 10 differ significantly from the data reported by Tolan et al; in particular, for the MCF-7 breast cancer cell line, IC 50 values for prodrug 10 in the study by Jin et al are 26-fold higher, and for the MDA-MB-231 triple negative breast adenocarcinoma cell line, IC 50 values are 21-fold higher than in the paper by Tolan et al ( Table 8 ) [ 28 ].…”

“…Recently, Jin et al described two cisplatin-based naproxen-containing platinum(IV) prodrugs [ 28 ]. Two highly potent cisplatin prodrugs with one (NP, 10 ) or two (DNP, 21 ) naproxen moieties in the axial position were obtained ( Figure 10 ).…”

“…An additional experiment in solution in the presence of 5′-GMP was conducted to verify the ability of prodrug 21 to form covalent adducts with DNA bases; no Pt-GMP or Pt-GMP 2 were detected by ESI-MS after 6 days of incubation. This led Jin et al to the assumption that complex 21 acts not as a prodrug, but as a whole complex that binds to DNA in a non-covalent manner [ 28 ].…”

“…Prodrug 10 was less efficient than prodrug 21 (75.5% tumor growth inhibition), but still inhibited tumor growth better than cisplatin (227 ± 71 and 660 ± 68 mm 3 tumor volume, respectively). No significant change in body weight was observed for the mice in all series [ 28 ].…”

Albumin-encapsulated Nanoparticles of Naproxen Platinum(IV) Complexes with Inflammation Inhibitory Competence Displaying Effective Antitumor Activities in vitro and in vivo

“… 39 More recently, Guo and Wang’s group reported the efficient antitumor performance of dual naproxen platinum(IV) complex 2 . 40 It targeted COX-2 and PD-L1 via multiple pathways to significantly inhibit the immune escape of tumor cells and finally improve antitumor efficacy. Thereby, naproxen platinum(IV) complex represents a promising scaffold for further development of novel platinum drugs.…”