In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 20 ( 2008-10-15), p. 8573-8581
Kurzfassung:
We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-α (TNF-α), 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 G1 cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-α, 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-α–mediated activation and translocation of nuclear factor-κB (NF-κB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-κB, 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 G1 phase of the cell cycle and could be a potential chemotherapeutic candidate. [Cancer Res 2008;68(20):8573–81]
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-08-2372
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2008
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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