Na, Yu-Ran Han, Ki-Cheol Park, Hyunsung Yang, Eun Gyeong 2024-01-20T12:30:30Z 2024-01-20T12:30:30Z 2021-09-05 2013-05-17 0006-291X https://pubs.kist.re.kr/handle/201004/128052 Hypoxia is a general characteristic of most solid malignancies and intimately related to neoplastic diseases and cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor (HIF)-1 alpha that elicits transcriptional activity through recruitment of the CREB binding protein (CBP)/p300 coactivator. Targeted blockade of HIF-1 alpha binding to CBP/p300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, we identified inhibitors against the interaction between HIF-1 alpha and p300 by a fluorescence polarization-based assay employing a fluorescently-labeled peptide containing the C-terminal activation domain of HIF-1 alpha. Two small molecule inhibitors, menadione (MD) and ethacrynic acid (EA), were found to decrease expression of luciferase under the control of hypoxia-responsive elements in hypoxic cells as well as to efficiently block the interaction between the full-length HIF-1 alpha and p300. While these compounds did not alter the expression level of HIF-1 alpha, they down-regulated expression of a HIF-1 alpha target vascular endothelial growth factor (VEGF) gene. Considering hypoxia-induced VEGF expression leading to highly aggressive tumor growth, MD and EA may provide new scaffolds for development of tumor therapeutic reagents as well as tools for a better understanding of HIF-1 alpha-mediated hypoxic regulation. (C) 2013 Elsevier Inc. All rights reserved. English ACADEMIC PRESS INC ELSEVIER SCIENCE ENDOTHELIAL GROWTH-FACTOR SIGNAL-TRANSDUCTION SMALL-MOLECULE IN-VIVO ANGIOGENESIS HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA CANCER DOMAIN CELLS FACTOR-1-ALPHA Menadione and ethacrynic acid inhibit the hypoxia-inducible factor (HIF) pathway by disrupting HIF-1 alpha interaction with p300 Article 10.1016/j.bbrc.2013.04.044 1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.434, no.4, pp.879 - 884 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 434 4 879 884 scie scopus 000320213200030 2-s2.0-84878211420 Biochemistry & Molecular Biology Biophysics Biochemistry & Molecular Biology Biophysics Article ENDOTHELIAL GROWTH-FACTOR SIGNAL-TRANSDUCTION SMALL-MOLECULE IN-VIVO ANGIOGENESIS HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA CANCER DOMAIN CELLS FACTOR-1-ALPHA Hypoxia inducible factor-1 alpha p300 Small molecule inhibitor Menadione Ethacrynic acid