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: Veena Coothankandaswamy, Yang Liu, Shui-Chun Mao, J Brian Morgan, Fakhri Mahdi, Mika B Jekabsons, Dale G Nagle, Yu-Dong Zhou
• Journal: Journal of natural products (J Nat Prod) Vol. 73 Issue 5 Pg. 956-61 (May 28 2010) ISSN: 1520-6025 [Electronic] United States
• PMID: 20423107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

• Acetogenins (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Asimina (chemistry)
• Complementary Therapies
• Drug Screening Assays, Antitumor
• Glucose Transporter Type 1 (analysis, drug effects, 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, drug effects, genetics)