Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
J Med Chem. 2021 Apr 8;64(7):4163-4178. doi: 10.1021/acs.jmedchem.1c00079. Epub 2021 Mar 30.
Cancer stem cells (CSCs) have a pivotal impact in drug resistance, tumor metastasis, and progression of various cancer entities, including in non-small cell lung cancer (NSCLC). A CK2 inhibitor was found to show potent CSC inhibitory effects in A549 cells. By taking advantage of inherent CK2 specificity and CSC inhibition of , a Pt(II) agent () was developed by conjugation of with an active Pt(II) unit to reverse cisplatin-induced resistance in A549/cDDP cell treatment. biological studies indicated that can target CK2, suppress DNA damage repair, reinforce cellular accumulation of platinum, and reverse resistance apart from effectively inhibiting CSCs through Wnt/β-catenin signal pathway in A549/cDDP cells. Significantly, presented an acceptable pharmacokinetic behavior and exhibited higher tumor growth inhibitory efficacy than cisplatin either in A549 or A549/cDDP xenograft models with low toxicity. Overall, is a promising drug candidate for NSCLC treatment.
肿瘤干细胞（CSCs）在多种癌症实体的耐药性、肿瘤转移和进展中具有关键作用，包括非小细胞肺癌（NSCLC）。研究发现，一种 CK2 抑制剂在 A549 细胞中显示出很强的 CSC 抑制作用。利用 CK2 的固有特异性和 CSC 抑制作用，通过将 与一个活性 Pt(II)单元连接，开发了一个 Pt(II)试剂 ()，以逆转 A549/cDDP 细胞治疗中顺铂诱导的耐药性。生物学研究表明， 可以靶向 CK2，抑制 DNA 损伤修复，增强细胞内铂的积累，并通过 A549/cDDP 细胞中的 Wnt/β-catenin 信号通路有效抑制 CSCs ，除了有效地抑制 CSCs 之外。此外， 在 A549 或 A549/cDDP 异种移植模型中， 表现出可接受的药代动力学行为，并显示出比顺铂更高的肿瘤生长抑制效果，且毒性较低。总的来说， 是一种很有前途的 NSCLC 治疗药物候选物。
