Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China.
Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P.R. China.
Dalton Trans. 2023 Sep 26;52(37):13097-13109. doi: 10.1039/d3dt02358c.
The development of novel anticancer drugs with antiproliferative and antimetastatic activities is of great importance in the pharmaceutical field. Herein, a series of ligustrazine (LSZ) platinum(IV) complexes with chemotherapeutic and immunotherapeutic effects were designed, prepared and evaluated as antitumor agents for the first time. Complex 4 with potent antitumor activities both and was screened out as a candidate. Notably, it displays significantly more effective anti-metastatic activities than the platinum(II) drugs cisplatin and oxaliplatin. Mechanism detection discloses that it causes serious DNA damage and increases the expression of γ-H2AX and P53. Then, the apoptosis of tumor cells is promoted by activating the mitochondrial apoptotic pathway Bcl-2/Bax/caspase-3 and causing autophagy modulating LC3-I/II and P62 expression. Furthermore, the immune therapeutic responses are significantly elevated by blocking HIF-1α, ERK 1/2 and COX-2 pathways to reduce PD-L1 expression, and further increasing CD3 and CD8 T cells to elevate T cell immunity in tumors. Tumor metastasis is blocked by the synergistic functions of DNA damage, hypoxia modulation and immune activation.
新型具有抗增殖和抗转移活性的抗癌药物的开发在制药领域具有重要意义。本文首次设计、制备和评价了一系列具有化疗和免疫治疗作用的川芎嗪（LSZ）铂（IV）配合物作为抗肿瘤剂。筛选出具有较强抗肿瘤活性的 4 号复合物 作为候选药物。值得注意的是，它显示出比顺铂和奥沙利铂等铂（II）药物更有效的抗转移活性。机制检测表明，它会导致严重的 DNA 损伤，增加 γ-H2AX 和 P53 的表达。然后，通过激活线粒体凋亡途径 Bcl-2/Bax/caspase-3 并导致自噬来促进肿瘤细胞的凋亡，调节 LC3-I/II 和 P62 的表达。此外，通过阻断 HIF-1α、ERK 1/2 和 COX-2 通路来抑制 PD-L1 的表达，显著提高免疫治疗反应，进一步增加肿瘤中的 CD3 和 CD8 T 细胞，从而提高 T 细胞免疫。通过 DNA 损伤、缺氧调节和免疫激活的协同作用阻断肿瘤转移。
