Cancer-selective antiproliferative activity is a general property of some G-rich oligodeoxynucleotides.
Cancer-selective antiproliferative activity is a general property of some G-rich oligodeoxynucleotides.
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DOI：
10.1093/nar/gkp1088
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发表时间：
2010-03
影响因子：
14.9
通讯作者：
Bates PJ
中科院分区：
文献类型：
--
作者：
Choi EW;Nayak LV;Bates PJ
含有随机结合碱基的寡脱氧核苷酸文库通过指数富集（SELEX）的配体系统进化产生DNA适体。我们预测具有不同碱基组成的组合库可能具有不同于含有等摩尔A + C + G + T碱基的标准库的固有性质。特别是，我们假设富含g的文库将包含更高比例的四重体形成序列，这可能赋予理想的品质，如增加核酸酶抗性和增强细胞摄取。在这里，我们报告了11种不同碱基组合和长度的合成寡脱氧核苷酸文库，关于它们的圆二色性，在含血清培养基中的稳定性，细胞摄取，蛋白质结合和抗增殖活性。出乎意料的是，我们发现一些富含G的文库（由G + T或G + C核苷酸组成）强烈抑制癌细胞生长，同时保留非恶性细胞。这些文库具有与g -四重体形成一致的光谱特征，在血清中比无活性文库更稳定，并显示出增强的细胞摄取。活性文库通常具有较强的蛋白质结合，而蛋白质结合模式表明G/T和G/C文库具有不同的作用机制。总之，癌症选择性抗增殖活性可能是某些富含g的寡脱氧核苷酸的一般特征，并与四重体形成、核酸酶抗性、有效的细胞摄取和蛋白质结合有关。
Oligodeoxynucleotide libraries containing randomly incorporated bases are used to generate DNA aptamers by systematic evolution of ligands by exponential enrichment (SELEX). We predicted that combinatorial libraries with alternative base compositions might have innate properties different from the standard library containing equimolar A + C + G + T bases. In particular, we hypothesized that G-rich libraries would contain a higher proportion of quadruplex-forming sequences, which may impart desirable qualities, such as increased nuclease resistance and enhanced cellular uptake. Here, we report on 11 synthetic oligodeoxynucleotide libraries of various base combinations and lengths, with regard to their circular dichroism, stability in serum-containing medium, cellular uptake, protein binding and antiproliferative activity. Unexpectedly, we found that some G-rich libraries (composed of G + T or G + C nucleotides) strongly inhibited cancer cell growth while sparing non-malignant cells. These libraries had spectral features consistent with G-quadruplex formation, were significantly more stable in serum than inactive libraries and showed enhanced cellular uptake. Active libraries generally had strong protein binding, while the pattern of protein binding suggested that G/T and G/C libraries have distinct mechanisms of action. In conclusion, cancer-selective antiproliferative activity may be a general feature of certain G-rich oligodeoxynucleotides and is associated with quadruplex formation, nuclease resistance, efficient cellular uptake and protein binding.
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