The antiproliferative agent MLN944 preferentially inhibits transcription

Sarah A Byers; Blanca Schafer; Darshan S Sappal; Jeffery Brown; David H Price

doi:10.1158/1535-7163.MCT-05-0109

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The antiproliferative agent MLN944 preferentially inhibits transcription

Journal article

Peer reviewed

The antiproliferative agent MLN944 preferentially inhibits transcription

Sarah A Byers, Blanca Schafer, Darshan S Sappal, Jeffery Brown and David H Price

Molecular cancer therapeutics, Vol.4(8), pp.1260-1267

08/2005

DOI: 10.1158/1535-7163.MCT-05-0109

PMID: 16093442

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Abstract

MLN944 is a novel compound currently being codeveloped by Millennium Pharmaceuticals and Xenova Ltd. as a cancer therapeutic and is in a phase I clinical trial for solid tumors. Although MLN944 was originally proposed to function as a topoisomerase I and II inhibitor, more recent data has shown that it is a DNA-intercalating agent that does not inhibit the catalytic activity of topoisomerase I or II. We show here that MLN944 inhibits incorporation of radiolabeled precursors into RNA preferentially over incorporation into DNA and protein in HCT116 and H460 cells. To determine if MLN944 inhibits transcription, a human RNA polymerase II in vitro transcription system was used. MLN944 inhibited initiation when added before or after the formation of preinitiation complexes and inhibited elongation at higher concentrations. The preferential inhibition of initiation differentiates MLN944 from actinomycin D, which more strongly inhibits elongation. Transcription of all RNA polymerases was inhibited in nuclei isolated from HeLa cells treated with low concentrations of MLN944. Our data are consistent with transcription as the target of the potent cytotoxic effects of MLN944.

Transcription, Genetic - drug effects

Nucleic Acid Synthesis Inhibitors - pharmacology

Phenazines - pharmacology

Humans

Antineoplastic Agents - pharmacology

Cell Proliferation - drug effects

RNA Polymerase II - metabolism

Tumor Cells, Cultured

Dactinomycin - pharmacology

Growth Inhibitors - pharmacology

Details

Title: Subtitle: The antiproliferative agent MLN944 preferentially inhibits transcription
Creators: Sarah A Byers - Department of Biochemistry, University of Iowa, 3130 MERF, Iowa City, IA 52242, USA
Blanca Schafer
Darshan S Sappal
Jeffery Brown
David H Price
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.4(8), pp.1260-1267
Publisher: United States
DOI: 10.1158/1535-7163.MCT-05-0109
PMID: 16093442
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: GM35500 / NIGMS NIH HHS
Language: English
Date published: 08/2005
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984024539002771

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