Activation of apoptosis by 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde, a novel compound from Aegle marmelos

Cancer Res. 2008 Oct 15;68(20):8573-81. doi: 10.1158/0008-5472.CAN-08-2372.


We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-alpha (TNF-alpha), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G(1) cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-alpha, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-alpha-mediated activation and translocation of nuclear factor-kappaB (NF-kappaB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-kappaB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G(1) phase of the cell cycle and could be a potential chemotherapeutic candidate.

Publication types

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

MeSH terms

  • Aegle / chemistry*
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Caspase 3 / metabolism
  • Cell Proliferation / drug effects
  • Cytochromes c / metabolism
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • G1 Phase / drug effects
  • HCT116 Cells
  • Humans
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • Naphthols / pharmacology*
  • Neoplasms, Experimental / drug therapy
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / analysis
  • TNF Receptor-Associated Death Domain Protein / genetics
  • TNF Receptor-Associated Death Domain Protein / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Vascular Endothelial Growth Factor A / genetics


  • 1-hydroxy-5,7-dimethoxy-2-naphthalenecarboxaldehyde
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Phytogenic
  • BH3 Interacting Domain Death Agonist Protein
  • NF-kappa B
  • Naphthols
  • Platelet Endothelial Cell Adhesion Molecule-1
  • RNA, Messenger
  • TNF Receptor-Associated Death Domain Protein
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 3