PMID- 19091749
OWN - NLM
STAT- MEDLINE
DCOM- 20090511
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 284
IP  - 9
DP  - 2009 Feb 27
TI  - Methylalpinumisoflavone inhibits hypoxia-inducible factor-1 (HIF-1) activation by 
      simultaneously targeting multiple pathways.
PG  - 5859-68
LID - 10.1074/jbc.M806744200 [doi]
AB  - Hypoxia is a common feature of solid tumors, and the extent of tumor hypoxia 
      correlates with advanced disease stages and treatment resistance. The 
      transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important 
      tumor-selective molecular target for anticancer drug discovery directed at tumor 
      hypoxia. A natural product chemistry-based approach was employed to discover 
      small molecule inhibitors of HIF-1. Bioassay-guided isolation of an active lipid 
      extract of the tropical legumaceous plant Lonchocarpus glabrescens and structure 
      elucidation afforded two new HIF-1 inhibitors: alpinumisoflavone (compound 1) and 
      4'-O-methylalpinumisoflavone (compound 2). In human breast tumor T47D cells, 
      compounds 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC(50) values 
      of 5 and 0.6 mum, respectively. At the concentrations that in hibited HIF-1 
      activation, compound 2 inhibited hypoxic induction of HIF-1 target genes (CDKN1A, 
      GLUT-1, and VEGF), tumor angiogenesis in vitro, cell migration, and chemotaxis. 
      Compound 2 inhibits HIF-1 activation by blocking the induction of nuclear 
      HIF-1alpha protein, the oxygen-regulated subunit that controls HIF-1 activity. 
      Mechanistic studies indicate that, unlike rotenone and other mitochondrial 
      inhibitors, compound 2 represents the first small molecule that inhibits HIF-1 
      activation by simultaneously suppressing mitochondrial respiration and disrupting 
      protein translation in vitro. This unique mechanism distinguishes compound 2 from 
      other small molecule HIF-1 inhibitors that are simple mitochondrial inhibitors or 
      flavanoid-based protein kinase inhibitors.
FAU - Liu, Yang
AU  - Liu Y
AD  - Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, 
      School of Pharmacy, and Department of Biology, University of Mississippi, 
      University, Mississippi 38677, USA.
FAU - Veena, Coothan K
AU  - Veena CK
FAU - Morgan, J Brian
AU  - Morgan JB
FAU - Mohammed, Kaleem A
AU  - Mohammed KA
FAU - Jekabsons, Mika B
AU  - Jekabsons MB
FAU - Nagle, Dale G
AU  - Nagle DG
FAU - Zhou, Yu-Dong
AU  - Zhou YD
LA  - eng
GR  - R01 CA098787-05A2/CA/NCI NIH HHS/United States
GR  - R01 CA098787-04/CA/NCI NIH HHS/United States
GR  - CA98787/CA/NCI NIH HHS/United States
GR  - P20RR021929/RR/NCRR NIH HHS/United States
GR  - C06 RR-14503-01/RR/NCRR NIH HHS/United States
GR  - R01 CA098787/CA/NCI NIH HHS/United States
GR  - R56 CA098787-05A1/CA/NCI NIH HHS/United States
GR  - R56 CA098787/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20081217
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (4'-O-methylalpinumisoflavone)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Glucose Transporter Type 1)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Isoflavones)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 6Q33HOF94Z (alpinumisoflavone)
SB  - IM
MH  - Blotting, Western
MH  - Breast Neoplasms/blood supply/drug therapy/metabolism
MH  - Cell Hypoxia
MH  - Cell Movement/*drug effects
MH  - Cell Proliferation
MH  - Cell Respiration/drug effects/physiology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Chemotaxis
MH  - Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism
MH  - Endothelium, Vascular/cytology/drug effects/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fabaceae/chemistry
MH  - Glucose Transporter Type 1/genetics/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism
MH  - Isoflavones/*pharmacology
MH  - Male
MH  - Mitochondria/drug effects/metabolism
MH  - Neovascularization, Pathologic
MH  - Oxygen Consumption/drug effects
MH  - Prostatic Neoplasms/blood supply/drug therapy/metabolism
MH  - Protein Biosynthesis
MH  - Umbilical Veins/cytology/drug effects/metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
MH  - Wound Healing
PMC - PMC2645834
EDAT- 2008/12/19 09:00
MHDA- 2009/05/12 09:00
PMCR- 2010/02/27
CRDT- 2008/12/19 09:00
PHST- 2008/12/19 09:00 [entrez]
PHST- 2008/12/19 09:00 [pubmed]
PHST- 2009/05/12 09:00 [medline]
PHST- 2010/02/27 00:00 [pmc-release]
AID - S0021-9258(20)70910-5 [pii]
AID - 5859 [pii]
AID - 10.1074/jbc.M806744200 [doi]
PST - ppublish
SO  - J Biol Chem. 2009 Feb 27;284(9):5859-68. doi: 10.1074/jbc.M806744200. Epub 2008 
      Dec 17.