Cytotoxicity of guanine-based degradation products contributes to the antiproliferative activity of guanine-rich oligonucleotides
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| Authors: | Nan Zhang Tao Bing Xiangjun Liu Cui Qi Luyao Shen Linlin Wang Dihua Shangguan |
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| Institution: | a Beijing National Laboratory for Molecular Sciences , Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry , Chinese Academy of Sciences , Beijing , 100190 , China . Email: ; Fax: +86-10-62528509 ; Tel: +86-10-62528509 ;b University of the Chinese Academy of Sciences , Beijing 100049 , China |
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| Abstract: | Guanine-rich oligonucleotides (GROs) have attracted considerable attention as anticancer agents, because they exhibit cancer-selective antiproliferative activity and can form G-quadruplex structures with higher nuclease resistance and cellular uptake. Recently, a GRO, AS1411 has reached phase II clinical trials for acute myeloid leukemia and renal cell carcinoma. The antiproliferative activity of GROs has been associated with various protein targets; however the real mechanisms of action remain unclear. In this study, we showed evidence that antiproliferative activity of GROs (including AS1411) is mainly contributed by the cytotoxicity of their guanine-based degradation products, such as monophosphate deoxyguanosine (dGMP), deoxyguanosine (dG) and guanine. The GROs with lower nuclease resistance exhibited higher antiproliferative activity. Among nucleotides, nucleosides and nucleobases, only guanine-based compounds showed highly concentration-dependent cytotoxicity. Our results suggest that it is necessary to reconsider the cancer-selective antiproliferative activity of GROs. Since guanine-based compounds are endogenous substances in living organisms, systematic studies of the cytotoxicity of these compounds will provide new information for the understanding of certain diseases and offer useful information for drug design. |
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