Arresting cancer proliferation by small-molecule gene regulation

被引：69

作者：

Dickinson, LA

Burnett, R

Melander, C

Edelson, BS

Arora, PS

Dervan, PB ^{[1
]}

Gottesfeld, JM

机构：

[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA

[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

来源：

CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 11期

关键词：

D O I：

10.1016/j.chembiol.2004.09.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A small library of pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugates was screened for effects on morphology and growth characteristics of a human colon carcinoma cell line, and a compound was identified that causes cells to arrest in the G2/M stage of the cell cycle. Microarray analysis indicates that the histone Hoc gene is significantly downregulated by this polyamide. RT-PCR and Western blotting experiments confirm this result, and siRNA to Hoc mRNA yields the same cellular response. Strikingly, reduction of H4 protein by >50% does not lead to widespread changes in global gene expression. Sequence-specific alkylation within the coding region of the Hoc gene in cell culture was confirmed by LM-PCR. The compound is active in a wide range of cancer cell lines, and treated cells do not form tumors in nude mice. The compound is also active in vivo, blocking tumor growth in mice, without obvious animal toxicity.

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页码：1583 / 1594

页数：12

相关论文

共 43 条

[1] Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids [J].

Baird, EE ;

Dervan, PB .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (26) :6141-6146

[2] Positive and negative regulation of endogenous genes by designed transcription factors [J].

Beerli, RR ;

Dreier, B ;

Barbas, CF .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (04) :1495-1500

[3] Cellular uptake of N-methylpyrrole/N-methylimidazole polyamide-dye conjugates [J].

Belitsky, JM ;

Leslie, SJ ;

Arora, PS ;

Beerman, TA ;

Dervan, PB .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (10) :3313-3318

[4] Nuclear localization of pyrrole-imidazole polyamide-fluorescein conjugates in cell culture [J].

Best, TP ;

Edelson, BS ;

Nickols, NG ;

Dervan, PB .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (21) :12063-12068

[5] Bifunctional alkylating agents derived from duocarmycin SA: Potent antitumor activity with altered sequence selectivity [J].

Boger, DL ;

Searcey, M ;

Tse, WC ;

Jin, Q .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (05) :495-498

[6] Novel antisense and peptide nucleic acid strategies for controlling gene expression [J].

Braasch, DA ;

Corey, DR .

BIOCHEMISTRY, 2002, 41 (14) :4503-4510

[7] Strand selective cleavage of DNA by diastereomers of hairpin polyamide-seco-CBI conjugates [J].

Chang, AY ;

Dervan, PB .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (20) :4856-4864

[8] IN-VIVO REPRESSION BY A SITE-SPECIFIC DNA-BINDING PROTEIN DESIGNED AGAINST AN ONCOGENIC SEQUENCE [J].

CHOO, Y ;

SANCHEZGARCIA, I ;

KLUG, A .

NATURE, 1994, 372 (6507) :642-645

[9] Expression profiling in multistage hepatocarcinogenesis: Identification of HSP70 as a molecular marker of early hepatocellular carcinoma [J].

Chuma, M ;

Sakamoto, M ;

Yamazaki, K ;

Ohta, T ;

Ohki, M ;

Asaka, M ;

Hirohashi, S .

HEPATOLOGY, 2003, 37 (01) :198-207

[10] Small-molecule-based strategies for controlling gene expression [J].

Denison, C ;

Kodadek, T .

CHEMISTRY & BIOLOGY, 1998, 5 (06) :R129-R145

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