Identification of a New G-Quadruplex Motif in the KRAS Promoter and Design of Pyrene-Modified G4-Decoys with Antiproliferative Activity in Pancreatic Cancer Cells

被引：76

作者：

Cogoi, Susanna ^{[1
]}

Paramasivam, Manikandan ^{[1
]}

Filichev, Vyacheslav ^{[2
]}

Geci, Imrich ^{[3
]}

Pedersen, Erik B. ^{[3
]}

Xodo, Luigi E. ^{[1
]}

机构：

[1] Sch Med, Dept Biomed Sci & Technol, I-33100 Udine, Italy

[2] Massey Univ, Inst Fundamental Sci, Palmerston North, New Zealand

[3] Univ So Denmark, Inst Chem & Phys, Nucle Acid Ctr, DK-5230 Odense M, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

关键词：

INTERCALATING NUCLEIC-ACIDS; INTRAMOLECULAR G-QUADRUPLEX; HUMAN GENOME; K-RAS; DNA; OLIGONUCLEOTIDES; INHIBITORS; NUCLEOLIN; THERAPY; LIGANDS;

D O I：

10.1021/jm800874t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new quadruplex motif located in the promoter of the human KRAS gene, within a nuclease hypersensitive element (NHE), has been characterized. Oligonucleotides mimicking this quadruplex are found to compete with a DNA-protein complex between NHE and a nuclear extract from pancreatic cancer cells. When modified with (R)-1-O-[4-1-(1-pyrenylethynyl) phenylmethyl]glycerol insertions (TINA), the quadruplex oligonucleotides showed a dramatic increase of the T-m (Delta T-m from 22 to 32 degrees C) and a strong antiproliferative effects in Panc-1 cells.

引用

页码：564 / 568

页数：5

共 23 条

[1] Pancreatic cancer biology and genetics [J].

Bardeesy, N ;

DePinho, RA .

NATURE REVIEWS CANCER, 2002, 2 (12) :897-909

[2] Antiproliferative activity of G-rich oligonucleotides correlates with protein binding [J].

Bates, PJ ;

Kahlon, JB ;

Thomas, SD ;

Trent, JO ;

Miller, DM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (37) :26369-26377

[3] Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: Small molecule regulation of c-kit oncogene expression [J].

Bejugam, Mallesham ;

Sewitz, Sven ;

Shirude, Pravin S. ;

Rodriguez, Raphael ;

Shahid, Ramla ;

Balasubramanian, Shankar .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129 (43) :12926-+

[4] Gene therapy developments for pancreatic cancer [J].

Bhattacharrya, M ;

Lemoine, NR .

BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, 2006, 20 (02) :285-298

[5] Intercalating nucleic acids containing insertions of 1-O-(1-pyrenylmethyl)glycerol:: stabilisation of dsDNA and discrimination of DNA over RNA [J].

Christensen, UB ;

Pedersen, EB .

NUCLEIC ACIDS RESEARCH, 2002, 30 (22) :4918-4925

[6] Structural polymorphism within a regulatory element of the human KRAS promoter:: formation of G4-DNA recognized by nuclear proteins [J].

Cogoi, Susanna ;

Paramasivam, Manikandan ;

Spolaore, Barbara ;

Xodo, Luigi E. .

NUCLEIC ACIDS RESEARCH, 2008, 36 (11) :3765-3780

[7] G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription [J].

Cogoi, Susanna ;

Xodo, Luigi E. .

NUCLEIC ACIDS RESEARCH, 2006, 34 (09) :2536-2549

[8] An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution [J].

Dai, JX ;

Dexheimer, TS ;

Chen, D ;

Carver, M ;

Ambrus, A ;

Jones, RA ;

Yang, DZ .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (04) :1096-1098

[9] Fluorescence-based melting assays for studying quadruplex ligands [J].

De Cian, Anne ;

Guittat, Lionel ;

Kaiser, Markus ;

Sacca, Barbara ;

Amrane, Samir ;

Bourdoncle, Anne ;

Alberti, Patrizia ;

Teulade-Fichou, Marie-Paule ;

Lacroix, Laurent ;

Mergny, Jean-Louis .

METHODS, 2007, 42 (02) :183-195

[10] Gene function correlates with potential for G4 DNA formation in the human genome [J].

Eddy, Johanna ;

Maizels, Nancy .

NUCLEIC ACIDS RESEARCH, 2006, 34 (14) :3887-3896

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