Methylalpinumisoflavone inhibits hypoxia-inducible factor-1 (HIF-1) activation by simultaneously targeting multiple pathways.
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.
Liu
Yang
Y
Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, and Department of Biology, University of Mississippi, University, Mississippi 38677, USA.
Veena
Coothan K
CK
Morgan
J Brian
JB
Mohammed
Kaleem A
KA
Jekabsons
Mika B
MB
Nagle
Dale G
DG
Zhou
Yu-Dong
YD
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007887:Fabaceae / Q000737:chemistry; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010101:Oxygen Consumption / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D014176:Protein Biosynthesis; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
C507553:4'-O-methylalpinumisoflavone; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007529:Isoflavones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000154:alpinumisoflavone