5/2/2023 0 Comments On1 effects 10.5 review![]() A high level of this protein is associated with increased cell proliferation, malignant transformation and progression, making the overexpression of surface nucleolin an indicator of a poor clinical prognosis. ![]() Surface nucleolin is mainly overexpressed on the membrane of cancer cells. The biological activity of AS1411 is related to its binding to nucleolin, a protein involved in cell survival, growth and proliferation. This G-quadruplex aptamer has attracted much attention and expectation in anticancer therapy because it demonstrates antiproliferative activity in many cell lines, such as breast, cervical and prostate cancer cell lines. One of the most studied anticancer aptamers and the most clinically advanced G-quadruplex is AS1411, first discovered by Bates et al. In particular, G-rich oligonucleotides are perceived as cancer-selective antiproliferative agents. G-quadruplexes have been extensively studied in recent years, and their various targets, such as cancer cells, viruses and proteins, were revealed. ![]() G-quadruplexes have several advantages compared with unstructured sequences, such as single-stranded DNA or RNA oligonucleotides, e.g., higher thermodynamic and chemical stability, improved cellular uptake, versatile chemical modification and low immunogenicity. Such molecules can recognize different proteins and inactivate their biological functions. However, synthetic G-rich oligonucleotides that form G-quadruplex structures have been demonstrated to be a promising therapeutic tool. ![]() Consequently, G-quadruplex structures constitute an attractive target in gene regulation therapeutic strategies. Importantly, such G-quadruplex triggers are perceived as key regulatory elements in pivotal cell processes, such as replication, transcription, translation and genome instability, and are often found in the promoter regions of cancer-related genes. Recently, several putative G-quadruplex-forming sequences were found in RNA and DNA fragments naturally occurring in living organisms. Understanding the G4 structural features and their role in the biological activity of G-rich molecules might facilitate the development of novel, more potent G4-based therapeutics with unprecedented anticancer properties. Thus, the ultimate antiproliferative potential of G4s is a net result of the specific balance among the structural features that are favorable for efficient uptake and those that increase the inhibitory activity of the studied molecules. Importantly, the structural requirements are different for efficient cancer cell line inhibition and favorable G4 cellular uptake. Various analyses have indicated that the G4 structural elements are intrinsic to the biological activity of these molecules. By contrast, highly structured G4s with an extended core containing four G-tetrads and longer loops are characterized by more efficient cellular uptake and improved biostability. The antiproliferative studies revealed that less thermodynamically stable G4s with three G-tetrads in the core and longer loops are more predisposed to effectively inhibit cancer cell growth. This systematic study aimed to investigate the anticancer potential of five G4-forming, sequence-related DNA molecules in terms of their thermodynamic and structural properties, biostability and cellular uptake. G-quadruplexes (G4s) are non-canonical structures formed by guanine-rich sequences of DNA or RNA that have attracted increased attention as anticancer agents.
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