Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1.
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.
Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Department of Pharmacology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Yong-Joon
YJ
Choi
Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Department of Pharmacology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Hyun-Woo
HW
Shin
Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Yang-Sook
YS
Chun
Department of Chemistry, Pukyong National University, Busan, 608-737, Republic of Korea.
Alain Simplice
AS
Leutou
Department of Chemistry, Pukyong National University, Busan, 608-737, Republic of Korea.
Byeng Wha
BW
Son
Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Department of Pharmacology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Jong-Wan
JW
Park
D000072283:A549 Cells; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000461:Rhodophyta / Q000737:chemistry; D015398:Signal Transduction; D014158:Transcription, Genetic; D014255:Trichothecenes / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014255:Trichothecenes; C001809:diacetoxyscirpenol
HIF-1; cancer; diacetoxyscirpenol; drug screening; hypoxia