Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P.R. China.
Liaocheng High-Tech Biotechnology Co., Ltd, Liaocheng 252059, P.R. China.
Dalton Trans. 2022 Aug 23;51(33):12604-12619. doi: 10.1039/d2dt00944g.
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 and exhibits much potential in overcoming drug resistance. More importantly, the antitumor evaluation 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 and CD8 T cells in tumor tissues.
为了开发新的抗转移化疗药物，我们制备并研究了一系列靶向 COX-2、PD-L1 和 DNA 的氟比洛芬（FLP）和扎托洛芬（ZTP）铂（IV）配合物。具有双重 FLP 配体的配合物 2 显示出有希望的抗肿瘤活性，并在克服耐药性方面具有很大的潜力。更重要的是，抗肿瘤评估表明，配合物 2 同时具有抑制肿瘤生长和转移的潜力。对机制的进一步研究揭示了配合物 2 的多特异性抗肿瘤功能。它在还原为铂（II）配合物后会产生显著的 DNA 损伤，并上调 p53 和 γ-H2AX 的表达。然后，配合物 2 通过激活 Bcl-2/Bax/caspase3 途径有效地促进线粒体介导的细胞凋亡。此外，通过抑制酶 COX-2、MMP-9、NLRP3 和 caspase1 来抑制肿瘤组织中的炎症，有利于抑制肿瘤转移。此外，化合物 2 通过抑制 PD-L1 的表达来增强 T 细胞免疫，并进一步提高肿瘤组织中 CD3 和 CD8 T 细胞的密度。
