Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX-2 and PD-L1.
Angew Chem Int Ed Engl
; 59(51): 23313-23321, 2020 12 14.
Article
in En
| MEDLINE
| ID: mdl-32897000
ABSTRACT
Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase-2 (COX-2) plays a vital role in the progression of BC, correlating with the expression of programmed death-ligand 1 (PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two 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. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple-negative 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. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Organoplatinum Compounds
/
Breast Neoplasms
/
Immunosuppression Therapy
/
Cyclooxygenase 2 Inhibitors
/
Inflammation
/
Antineoplastic Agents
Type of study:
Diagnostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2020
Document type:
Article