title: The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway.
abstract: 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.
authors.affiliation: Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Coothankandaswamy
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Shui-Chun
authors.initials: SC
authors.lastname: Mao
authors.forename: J Brian
authors.initials: JB
authors.lastname: Morgan
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Mika B
authors.initials: MB
authors.lastname: Jekabsons
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
mesh_terms: D054378:Acetogenins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D031042:Asimina / Q000737:chemistry*; D000529:Complementary Therapies; D004354:Drug Screening Assays, Antitumor; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010946:Plants, Medicinal / Q000737:chemistry*; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000187:drug effects* / Q000235:genetics
chemical_list: D054378:Acetogenins; D000972:Antineoplastic Agents, Phytogenic; D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D042442:Vascular Endothelial Growth Factors