The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway

J Nat Prod. 2010 May 28;73(5):956-61. doi: 10.1021/np100228d.


Products that contain twig extracts of pawpaw (Asimina triloba) are widely consumed anticancer alternative medicines. Pawpaw crude extract (CE) and purified acetogenins inhibited hypoxia-inducible factor-1 (HIF-1)-mediated hypoxic signaling pathways in tumor cells. In T47D cells, pawpaw CE and the acetogenins 10-hydroxyglaucanetin (1), annonacin (2), and annonacin A (3) inhibited hypoxia-induced HIF-1 activation with IC(50) values of 0.02 microg/mL, 12 nM, 13 nM, and 31 nM, respectively. This inhibition correlates with the suppression of the hypoxic induction of HIF-1 target genes VEGF and GLUT-1. The induction of secreted VEGF protein represents a key event in hypoxia-induced tumor angiogenesis. Both the extract and the purified acetogenins blocked the angiogenesis-stimulating activity of hypoxic T47D cells in vitro. Pawpaw extract and acetogenins inhibited HIF-1 activation by blocking the hypoxic induction of nuclear HIF-1alpha protein. The inhibition of HIF-1 activation was associated with the suppression of mitochondrial respiration at complex I. Thus, the inhibition of HIF-1 activation and hypoxic tumor angiogenesis constitutes a novel mechanism of action for these anticancer alternative medicines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetogenins / chemistry
  • Acetogenins / isolation & purification*
  • Acetogenins / pharmacology*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Asimina / chemistry*
  • Complementary Therapies
  • Drug Screening Assays, Antitumor
  • Glucose Transporter Type 1 / analysis
  • Glucose Transporter Type 1 / drug effects*
  • Glucose Transporter Type 1 / genetics
  • Humans
  • Hypoxia-Inducible Factor 1 / drug effects*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Neovascularization, Physiologic / drug effects*
  • Plants, Medicinal / chemistry*
  • Vascular Endothelial Growth Factors / analysis
  • Vascular Endothelial Growth Factors / drug effects*
  • Vascular Endothelial Growth Factors / genetics


  • Acetogenins
  • Antineoplastic Agents, Phytogenic
  • Glucose Transporter Type 1
  • Hypoxia-Inducible Factor 1
  • Vascular Endothelial Growth Factors