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Oligomannurarate sulfate blocks tumor growth by inhibiting NF-kappaB activation.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2010 Mar; Vol. 31 (3), pp. 375-81. Date of Electronic Publication: 2010 Feb 15. - Publication Year :
- 2010
-
Abstract
- Aim: JG3, a novel marine-derived oligosaccharide, significantly inhibits angiogenesis and tumor metastasis by blocking heparanase activity. It also arrests tumor growth, an effect that is not fully explained by its anti-heparanase activity. Here we sought to identify the mechanisms underlying JG3-mediated inhibition of tumor growth.<br />Methods: Heparanase expression was assessed by RT-PCR and Western blotting. NF-kappaB activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-kappaB pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-kappaB activation were evaluated using four different tumor xenograft models.<br />Results: We found that JG3 effectively inhibited NF-kappaB activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-kappaB by interfering with the activation of upstream components of the NF-kappaB pathway without generally affecting the nuclear translocation of transcription factors. Further, in vivo studies demonstrated that JG3 effectively arrested the growth of tumors derived from cell lines in which NF-kappaB was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-kappaB-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma).<br />Conclusion: Our data indicate that NF-kappaB mediates the JG3-induced arrest of tumor growth. These results define a new mechanism of action of JG3 and highlight the potential for JG3 as a promising lead molecule in cancer therapy.
- Subjects :
- Angiogenesis Inhibitors pharmacology
Animals
Cell Line, Tumor
Heparin Lyase metabolism
Humans
Mannans pharmacology
Mice
Mice, Nude
Neoplasms pathology
Signal Transduction drug effects
Angiogenesis Inhibitors therapeutic use
Mannans therapeutic use
NF-kappa B antagonists & inhibitors
NF-kappa B metabolism
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 31
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 20154712
- Full Text :
- https://doi.org/10.1038/aps.2010.13