Oncogene Promoter G-Quadruplexes As Potential Therapeutic Targets Towards Effective New Anticancer Drug Design
- سال انتشار: 1395
- محل انتشار: دومین سمپوزیوم بین المللی سرطان نسترن
- کد COI اختصاصی: NASTARANCANSER02_090
- زبان مقاله: انگلیسی
- تعداد مشاهده: 472
نویسندگان
Department Of Molecular And Cell Biology, Faculty Of Basic Sciences, University Of Mazandaran, Babolsar , Iran
Department Of Molecular And Cell Biology, Faculty Of Basic Sciences, University Of Mazandaran, Babolsar, Iran ۲ Nano AndBiotechnology Research Group, Faculty Of Basic Sciences, University Of Mazandaran, Babolsar, Iran
چکیده
Besides the B-form canonical duplexes, DNA can fold into different other inter- and intramolecularsecondary structures. DNA G-quadruplexes are higher order structures formed in specific G-richsequences which can assemble into tetrameric structures. G- quadruplexes are over-represented inoncogenes promoter and other regions within the genome with biologically significant role.Attention to the more common therapeutic importance of G-quadruplexes has extended throughthe past decade and they studied as a new class of novel molecular therapeutic targets in oncology,wherever transcriptional down regulation of oncogenes via stabilization of these structures couldbe a novel anticancer approach. Recently, researchers have had special interest to find out smallmolecules that could stabilize these higher order structures, not only by modifying the stability ofG-quadruplexes and down regulation of oncogenes expression but also by performing so selectivelyin the presence of other possible targets such as double-stranded DNA. This interest was triggeredby 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 inpromoter regions. For the first time we have successfully down-regulated the WT1 oncogeneexpression in AML leukemia cell line by using this technology in Iran. These findings prepare thefoundation for the rational design and improvement of G-quadruplex-stabilizing molecules as newanticancer drugs for targeted cancer therapy which selectively have an antiproliferative andchemosensitizing activity in in vitro and in vivo tumor models, without any noticeable influence onnormal cells. In addition the different molecular structures of G-quadruplexes revealed they maybe differentially regulated and targeted by different molecules and much studies are being made toimprove selection of small molecules with developed G-quadruplex detection and to efficientlyaffect target gene transcription. In conclusion, the biological significance of promoter Gquadruplexeshas strengthened investigation and improvement of G-quadruplex-interactivemolecules, as potential anticancer drugs which reveal approximately lower cytotoxicity in normalcells. Some of the G-quadruplex targeting drugs have entered Phase II clinical trials.کلیدواژه ها
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