Acta Pharmacologica Sinica (2010) 31: 375–381; doi: 10.1038/aps.2010.13; published online 15 February 2010

Jing ZHANG, Yi CHEN, Xian-liang XIN, Qiu-ning LI, Ming LI, Li-ping LIN, Mei-yu GENG^*, Jian DING^*

Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

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. 

Methods: Heparanase expression was assessed by RT-PCR and Western blotting.  NF-κB activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays.  The effect of JG3 on upstream components of the NF-κB pathway and on selected transcription factors were monitored by Western blotting.  The antitumor effect of JG3 and its relation to NF-κB activation were evaluated using four different tumor xenograft models.

Results: We found that JG3 effectively inhibited NF-κB activation independent of heparanase expression.  Our results indicate that JG3 inactivated NF-κB by interfering with the activation of upstream components of the NF-κB 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-κB was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-κB-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma).

Conclusion: Our data indicate that NF-κB 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.

Keywords: oligosaccharide sulfate; NF-κB inhibitors; tumor growth; heparanase; liver neoplasm; breast neoplasm