Oncotarget

Research Papers:

Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1

Yong-Joon Choi, Hyun-Woo Shin, Yang-Sook Chun, Alain Simplice Leutou, Byeng Wha Son and Jong-Wan Park _

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Oncotarget. 2016; 7:62107-62122. https://doi.org/10.18632/oncotarget.11529

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Abstract

Yong-Joon Choi1,2, Hyun-Woo Shin1,2,3,4, Yang-Sook Chun1,3, Alain Simplice Leutou5, Byeng Wha Son5, Jong-Wan Park1,2,3,4

1Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea

2Department of Pharmacology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea

3Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea

4Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea

5Department of Chemistry, Pukyong National University, Busan, 608-737, Republic of Korea

Correspondence to:

Jong-Wan Park, email: [email protected]

Keywords: cancer, hypoxia, HIF-1, drug screening, diacetoxyscirpenol

Received: June 09, 2016     Accepted: August 15, 2016     Published: August 23, 2016

ABSTRACT

Hypoxia activates hypoxia-inducible factor 1, which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. Thus, HIF-1 is one of the most compelling targets for treating cancers. The aim of this study was to find a small molecule that inhibits HIF-1 under hypoxia in cancer cells. 7,280 compounds in a chemical library were tested in a cancer cell line expressing luciferase HIF-dependently. Through three rounds of screening, we finally picked up a compound that originates from a marine bacterium parasitizing red alga. The antibiotic potently inhibited HIF-1 expression and its transcriptional activity in cancer cells exposed to hypoxia. Through two-step fractionation, diacetoxyscirpenol was purified and identified as a HIF-inhibiting ingredient. Mechanistically, diacetoxyscirpenol inhibits the synthesis of HIF-1α protein and also interferes with the dimerization of HIF-1α and ARNT. It attenuates HIF-mediated gene expression in cancer cells exposed to hypoxia, and by doing so reduces tumorigenic and angiogenic potentials of cancer cells. More importantly, diacetoxyscirpenol retarded tumor growth in mice, and reduced HIF-1α expression and vascular formation in the tumors. Overall, diacetoxyscirpenol is considered a potential drug deregulating the HIF-1 signaling pathway, and it could be beneficially employed for treating malignant tumors with hypoxic microenvironment.


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