Summary
Oligonucleotides with guanosine-rich (G-rich) sequences often have unusual physical and biological properties, including resistance to nucleases, enhanced cellular uptake, and high affinity for particular proteins. Furthermore, we have found that certain G-rich oligonucleotides (GROs) have antiproliferative activity against a range of cancer cells, while having minimal toxic effects on normal cells. We have investigated the mechanism of this activity and studied the relationship between oligonucleotide structural features and biological activity. Our results indicate that the antiproliferative effects of GROs depend on two properties: the ability to form quadruplex structures stabilized by G-quartets and binding affinity for nucleolin protein. Thus, it appears that the antiproliferative GROs are acting as nucleolin aptamers. Because nucleolin is expressed at high levels on the surface of cancer cells, where it mediates the endocytosis of various ligands, it seems likely that nucleolin-dependent uptake of GROs plays a role in their activity. One of the GROs that we have developed, a 26-nucleotide phosphodiester oligodeoxynucleotide now named AS1411 (formerly AGRO100 or GRO26B-OH), is currently being tested as an anticancer agent in Phase II clinical trials.
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References
Opalinska JB, Gewirtz AM. (2002) Nucleic-acid therapeutics: basic principles and recent applications. Nat Rev Drug Discov. 1:503–14.
Gleave ME, Monia BP. (2005) Antisense therapy for cancer. Nat Rev Cancer 5:468–79.
Scherer LJ, Rossi JJ. (2003) Approaches for the sequence-specific knockdown of mRNA. Nat Biotechnol 21:1457–65.
Mahato RI, Cheng K, Guntaka RV. (2005) Modulation of gene expression by antisense and antigene oligodeoxynucleotides and small interfering RNA. Expert Opin Drug Deliv 2:3–28.
Devi GR. (2006) siRNA-based approaches in cancer therapy. Cancer Gene Ther 13:819–29.
Tomita N, Ogihara T, Morishita R. (2003) Transcription factors as molecular targets: molecular mechanisms of decoy ODN and their design. Curr Drug Targets 4:603–8.
Krieg AM. (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–7.
Nimjee SM, Rusconi CP, Sullenger BA. (2005) Aptamers: an emerging class of therapeutics. Annu Rev Med 56:555–83.
Chu T, Ebright J, Ellington AD. (2007) Using aptamers to identify and enter cells. Curr Opin Mol Ther 9:137–44.
Ireson CR, Kelland LR. (2006) Discovery and development of anticancer aptamers. Mol Cancer Ther 5:2957–62.
Bates PJ, Kahlon JB, Thomas SD, Trent JO, Miller DM. (1999) Antiproliferative activity of G-rich oligonucleotides correlates with protein binding. J Biol Chem 274:26369–77.
Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG, Trent JO, Miller DM, Bates PJ. (2001) Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J Biol Chem 276:43221–30.
Dapić V, Bates PJ, Trent JO, Rodger A, Thomas SD, Miller DM. (2002) Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications. Biochemistry 41:3676–85.
Dapić V, Abdomerović V, Marrington R, Peberdy J, Rodger A, Trent JO, Bates PJ. (2003) Biophysical and biological properties of quadruplex oligodeoxyribonucleotides. Nucleic Acids Res 31:2097–107.
McMicken HW, Bates PJ, Chen Y. (2003) Antiproliferative activity of G-quartet-containing oligonucleotides generated by a novel single-stranded DNA expression system. Cancer Gene Ther 10:867–9.
Girvan AC, Teng Y, Casson LK, Thomas SD, Jüliger S, Ball MW, Klein JB, Pierce WM Jr, Barve SS, Bates PJ. (2006) AGRO100 inhibits activation of nuclear factor-kappaB (NF-kappaB) by forming a complex with NF-kappaB essential modulator (NEMO) and nucleolin. Mol Cancer Ther 5:1790–9.
Teng Y, Girvan AC, Casson LK, Pierce WM Jr, Qian M, Thomas SD, Bates PJ. (2007) AS1411 alters the localization of a complex containing protein arginine methyltransferase 5 and nucleolin. Cancer Res 67:10491–500.
Laber D, Bates P, Trent J, Barnhart K, Taft B, Miller D. (2005) Long term clinical response in renal cell carcinoma patients treated with quadruplex forming oligonucleotides. Clin Cancer Res 11:9088S
Miller D, Laber D, Bates P, Trent J, Taft B, Kloecker GH. (2006) Extended phase I study of AS1411 in renal and non-small cell lung cancers. Ann Oncol 17(Suppl 8):ix147–8.
Dignam JD, Lebovitz RM, Roeder RG. (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–89.
Acknowledgments and Disclosures
The work described herein was funded in part by the US National Cancer Institute and the US Department of Defense Prostate Cancer Program. In addition to these sources, the authors currently receive or have previously received funding from the Kentucky Lung Cancer Research Program, the Komen Breast Cancer Foundation, the University of Louisville, and Antisoma PLC (London, England). Paula J. Bates owns shares in Antisoma.
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Bates, P.J., Choi, E.W., Nayak, L. (2009). G-Rich Oligonucleotides for Cancer Treatment. In: Walther, W., Stein, U. (eds) Gene Therapy of Cancer. Methods in Molecular Biology™, vol 542. Humana Press. https://doi.org/10.1007/978-1-59745-561-9_21
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DOI: https://doi.org/10.1007/978-1-59745-561-9_21
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