Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo
Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo
复制标题
抗癌 Melatplatin 前药：高效低毒、MT1-ER 靶点和体内免疫反应
DOI：
10.1021/acs.jmedchem.0c00343
复制
发表时间：
2020-06-11
影响因子：
7.3
通讯作者：
Xu, Jing-Yuan
中科院分区：
文献类型：
--
作者：
Song, Xue-Qing;Liu, Rui-Ping;Xu, Jing-Yuan
多靶点治疗可以纠正多种致癌途径，阻断肿瘤的发生和发展。内分泌、免疫和化疗的联合可能对某些肿瘤产生高度的协同作用。在此，一系列的智能铂（IV）前药3-6，命名为美拉铂，合理设计，不仅多靶点DNA，MT 1，和雌激素受体（ER），而且激活免疫反应。将一线化疗铂类药物与人内源性褪黑激素（MT）结合的美拉铂显著增强了药物疗效，尤其是在ER高表达（ER+）细胞中，其中3对ER+ MCF-7表现出最强的细胞毒性，其纳摩尔IC 50值比顺铂低100倍。分子对接结果表明，褪黑素与褪黑素受体（MT 1）结合良好。此外，3明显增加细胞内积累和DNA损伤，上调γ H2 AX和P53，并沉默NF-κ B B，诱导大量凋亡。最引人注目的是，3在体内有效地抑制肿瘤生长，与顺铂相比减轻全身毒性，促进脾中淋巴细胞增殖以实现免疫调节。
Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3-6, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER+) cells, among which 3 presented the most potent cytotoxicity toward ER+ MCF-7 with nanomolar IC50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated gamma H2AX and P53, and silenced NF-kappa B to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo, promoting lymphocyte proliferation in spleen to achieve immune modulation.