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Abstract
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Besides the B-form canonical duplexes, DNA can fold into different other inter- and intramolecular secondary structures. DNA G-quadruplexes are higher order structures formed in specific G-rich sequences which can assemble into tetrameric structures. G- quadruplexes are over-represented in oncogenes promoter and other regions within the genome with biologically significant role. Attention to the therapeutic importance of G-quadruplexes has been paid since the past decade. Recently, researchers have special interest to find out small molecules that could stabilize these higher order structures, not only by modifying the stability of G-quadruplexes and down regulation of oncogenes expression but also by performing so selectively in the presence of other possible targets such as double-stranded DNA. This interest was triggered by publications displaying the transcriptional repression of the c-MYC, c-KIT, PDGF-A, bcl-2, VEGF, Hif-1α, STAT3, HRAS and WT1 proto-oncogene genes through stabilization of these structures in promoter regions. For the first time we have successfully down-regulated the WT1 oncogene expression in AML leukemia cell line by using this technology. Wilms’ tumor gene 1 (WT1) encodes a zinc-finger transcription factor, originally recognized as a tumor suppressor gene in a pediatric kidney cancer, Wilms’ tumor. The knockdown of WT1 powerfully stimulates the apoptosis of leukemic cells and blocks malignant cell growth. WT1 has a role in immune function, angiogenesis, cell apoptosis, adhesion and differentiation. WT1 is overexpressed (5–10 times above background levels) in 86% of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and acute lymphoblastic leukemia (ALL) and a variety of solid cancers, but not in the normal cells, WT1 is now considered as a potential oncogene and a favorable target for cancer treatment. According to the Greglist, a database listing for quadruplex forming G-rich sequences (QGRS), theoretically many on
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