The antiproliferative agent MLN944 preferentially inhibits transcription

被引:20
作者
Byers, SA
Schafer, B
Sappal, DS
Brown, J
Price, DH
机构
[1] Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA
[2] Univ Iowa, Program Mol Biol, Iowa City, IA 52242 USA
[3] Millennium Pharmaceut Inc, Dept Mol & Cellular Oncol, Cambridge, MA USA
关键词
D O I
10.1158/1535-7163.MCT-05-0109
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 11 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.
引用
收藏
页码:1260 / 1267
页数:8
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