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共价双模块平行和反平行 G-四链体 DNA 纳米结构降低患者神经胶质瘤原代细胞培养物的活力。

Covalent Bi-Modular Parallel and Antiparallel G-Quadruplex DNA Nanocostructs Reduce Viability of Patient Glioma Primary Cell Cultures.

机构信息

Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia.

Burdenko Neurosurgical Institute, 125047 Moscow, Russia.

出版信息

Int J Mol Sci. 2021 Mar 25;22(7):3372. doi: 10.3390/ijms22073372.

DOI:10.3390/ijms22073372
PMID:33806042
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8036578/
Abstract

G-quadruplex oligonucleotides (GQs) exhibit specific anti-proliferative activity in human cancer cell lines, and they can selectively inhibit the viability/proliferation of cancer cell lines vs. non-cancer ones. This ability could be translated into a cancer treatment, in particular for glioblastoma multiform (GBM), which currently has a poor prognosis and low-efficiency therapeutic treatments. A novel bi-modular GQ, bi-(AID-1-T), a twin of the previously described three-quartet AID-1-T, was designed and studied in terms of both its structure and function. A covalent conjugation of two AID-1-Ts via three thymidine link, TTT, did not interfere with its initial GQ structure. A comparison of bi-(AID-1-T) with its mono-modular AID-1-T, mono-modular two-quartet HD1, and bi-modular bi-HD1, as well as conventional two-quartet AS1411, was made. Among the five GQs studied, bi-(AID-1-T) had the highest anti-proliferative activity for the neural cancer cell line U87, while not affecting the control cell line, human embryonic fibroblasts. GQs, for the first time, were tested on several primary glioma cultures from patient surgical samples. It turned out that the sensitivity of the patient primary glioma cultures toward GQs varied, with an apparent IC of less than 1 μM for bi-(AID-1-T) toward the most sensitive G11 cell culture (glioma, Grade III).

摘要

G-四链体寡核苷酸（GQs）在人类癌细胞系中表现出特定的抗增殖活性，并且可以选择性地抑制癌细胞系的活力/增殖，而对非癌细胞系没有影响。这种能力可以转化为癌症治疗方法，特别是针对多形性胶质母细胞瘤（GBM），目前其预后较差，治疗效果不佳。一种新型双模块 GQ，双-(AID-1-T)，是之前描述的三四重 AID-1-T 的孪生体，在结构和功能方面都进行了设计和研究。通过三个胸腺嘧啶键，TTT，将两个 AID-1-T 共价连接在一起，不会干扰其初始 GQ 结构。将双-(AID-1-T)与其单模块 AID-1-T、单模块二四重体 HD1 和双模块双-HD1 以及常规二四重体 AS1411 进行了比较。在所研究的五种 GQs 中，双-(AID-1-T)对神经癌细胞系 U87 的增殖活性最高，而对对照细胞系人胚胎成纤维细胞没有影响。GQs 首次在来自患者手术样本的几种原发性脑肿瘤培养物上进行了测试。结果表明，患者原发性脑肿瘤培养物对 GQs 的敏感性不同，对于最敏感的 G11 细胞培养物（胶质瘤，III 级），双-(AID-1-T) 的 IC 值明显低于 1 μM。

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