The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway.
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.
Coothankandaswamy
Veena
V
Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Liu
Yang
Y
Mao
Shui-Chun
SC
Morgan
J Brian
JB
Mahdi
Fakhri
F
Jekabsons
Mika B
MB
Nagle
Dale G
DG
Zhou
Yu-Dong
YD
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
D054378:Acetogenins; D000972:Antineoplastic Agents, Phytogenic; D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D042442:Vascular Endothelial Growth Factors