Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance
Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance
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DOI：
10.1016/j.bbrc.2019.10.184
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发表时间：
2020-01-15
影响因子：
3.1
通讯作者：
Gou, Shaohua
中科院分区：
文献类型：
--
作者：
Chen, Feihong;Pei, Sinan;Gou, Shaohua
由顺铂或DN 604与CK 2抑制剂CX-4945偶联得到的两种Pt（IV）前药Cx-铂-Cl和Cx-DN 604-Cl被构建用于抑制DNA损伤修复相关元件。在体外生物学研究期间，Pt（IV）前药具有上级顺铂和DN 604的优异的细胞毒性以逆转耐药性。进一步的机制研究表明，Cx-铂-Cl和Cx-DN 604-Cl的强大抗癌活性源于其抑制JWA-XRCC 1介导的单链断裂修复。除了JWA（-/-）小鼠外，新出现的Pt（IV）前药抑制C57 BL 6和裸鼠的异种移植肿瘤的生长。其中，Cx-platin-Cl促进了T-eff细胞的浸润和增殖，抑制了Treg细胞的募集。结果提供了令人信服的临床前支持，即Cx-铂-Cl和Cx-DN 604-Cl可以通过衰减JWA-XRCC 1介导的SSBR和免疫抑制来逆转化学免疫抗性，从而改善了新兴Pt（IV）候选物作为用于癌症抗性预防的潜在免疫抑制剂的开发。(C)2019爱思唯尔公司All rights reserved.
Two Pt(IV) prodrugs, Cx-platin-Cl and Cx-DN604-Cl, derived from the conjugation of cisplatin or DN604 with a CK2 inhibitor CX-4945, were constructed to suppress DNA damage repair-related elements. During in vitro biological studies, the Pt(IV) prodrugs had excellent cytotoxicity superior to cisplatin and DN604 to reverse drug resistance. Further mechanistic investigations revealed that the powerful anticancer activity of Cx-platin-Cl and Cx-DN604-Cl arisen from its suppression of JWA-XRCC1-mediated single-strand breaks repair. The emerging Pt(IV) prodrugs inhibited the growth of the xenografted tumors of C57BL6 and nude mice apart from JWA(-/-) mice. Between them, Cx-platin-Cl augmented the infiltration and proliferation of T-eff cells, alleviated the recruitment of Treg cells. The results provided compelling preclinical support that Cx-platin-Cl and Cx-DN604-Cl could reverse chemo-immune resistance via decaying JWA-XRCC1-mediated SSBR and immunosuppression, improving the development of emerging Pt(IV) candidate as a potential immunotherapeutic agent for cancer resistant prevention. (C) 2019 Elsevier Inc. All rights reserved.