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Development of a series of flurbiprofen and zaltoprofen platinum(IV) complexes with anti-metastasis competence targeting COX-2, PD-L1 and DNA.
- Source :
-
Dalton transactions (Cambridge, England : 2003) [Dalton Trans] 2022 Aug 23; Vol. 51 (33), pp. 12604-12619. Date of Electronic Publication: 2022 Aug 23. - Publication Year :
- 2022
-
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 <superscript>+</superscript> and CD8 <superscript>+</superscript> T cells in tumor tissues.
Details
- Language :
- English
- ISSN :
- 1477-9234
- Volume :
- 51
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- Dalton transactions (Cambridge, England : 2003)
- Publication Type :
- Academic Journal
- Accession number :
- 35924963
- Full Text :
- https://doi.org/10.1039/d2dt00944g