The Experiment Study Of The Inhibition Effects Of Isomalto Oligosaccharide Sulfate On Tumor Growth And Metastasis Of Human Hepatocellular Carcinoma

The experiment study of the inhibition effects of isomalto oligosaccharide sulfate on tumor growth and metastasis of human hepatocellular carcinomaHepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death globally. As indicated in statistics, the disease is diagnosed in 30% to 40% of all patients at early stages and about 20% of all patients are amenable to curative therapies, such as resection, liver transplantation, and radiofrequency ablation. Five-year survival rates of up to 60% to 70% have been achieved in well-selected patients. However, HCC at advanced stages usually carries a dismal prognosis because of liver dysfunction, lack of effective treatment options, and a high metastatic rate. Therefore, it is urgent to explore new therapeutic options for patients with advanced HCC.Heparanase inhibitor has recently become an attractive agent for highly malignant tumors, due to its antiangiogenic and antimetastatic activities. Two representatives, phosphomannopentaose sulfate (PI-88) and oligomannurarate sulfate (JG3), were reported to have inhibitory effects on tumor growth and metastasis. Phase 1 and 2 trials of PI-88 have been finished and have shown potential antitumor effects.Two distinctive differences in molecular structure exist between isomalto oligosaccharide sulfate (IMOS) and PI-88. IMOS is composed of four sulfated isomaltose molecules with a molecular weight<1500 Da, whereas PI-88 is composed of five sulfated mannose molecules with a molecular weight of 2100 to 2585 Da. Such alterations in structure may affect its toxicity and antitumor effects. In this report, we present our preliminary evidence of the effects of IMOS on experimental HCC growth and metastasis.1. The effects of Isomalto Oligosaccharide Sulfate on HCC proliferation,apoptosis, adhesion, migration, and invasiveness in vitro Objective:We explored the effects of isomalto oligosaccharide sulfate (IMOS) on HCC proliferation, apoptosis, adhesion, migration, and invasiveness. Methods:The effects of IMOS on HCC proliferation, apoptosis, adhesion, migration, and invasiveness in vitro were assessed by cell counting, flow cytometry, adhesion, wound healing, and transwell assays, respectively. Results:IMOS markedly inhibited cell proliferation and induced cell apoptosis of HCCLM3, HepG2, and Bel-7402 cells and also significantly suppressed cell adhesion, migration, and invasion of HCCLM3 in vitro. Conclusion:IMOS is a potential anti-HCC candidate and worth studying further in xenograft nude mice models in vivo.2. The effects of Isomalto Oligosaccharide Sulfate on HCCLM3 xenograft growth and metastasis in nude miceObjective:To explore the effects of Isomalto oligosaccharide sulfate on HCCLM3 xenograft growth and metastasis in nude mice. Methods:Body weights, hepatorenal functions and pathologic examinations of important organs of nude mice were assessed when IMOS was intraperitoneally injected using a dose-escalation strategy. HCCLM3 xenograft growths in 0,30,60 or 90 mg/kg/d IMOS treated mice were dynamically measured once a week by fluorescent stereomicroscope. The roles of IMOS on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. Results:A robust inhibitory effect on HCCLM3 xenograft growth and metastasis without obvious toxicities was observed when IMOS was administered at the dosage of no more than 90 mg/kg/d.Conclusions:IMOS could be a potential anti-HCC agent and worth further studies in patients with HCC, especially disease at advanced stages. 3. The mechanism of the inhibition effects of isomalto oligosaccharide sulfate on tumor growth and metastasis of human hepatocellular carcinomaObjective:To investigate the underlying molecular mechanism of IMOS inhibitory effects on HCC growth and metastasis.Methods:Total and phosphorylated protein levels of AKT, ERK, and JNK as well as total levels of c-MET were detected by Western blotting. IMOS-regulated genes were screened by Supperarray in HCCLM3-red fluorescent protein (RFP) xenograft tissues and then confirmed by quantitative reverse-transcription PCR (qRT-PCR) in HepG2 and Hep3B cells. Results:The results showed that the levels of pERK, tERK, and pJNK as well as c-MET were significantly down-regulated after treatment with 16 mg/mL IMOS. No obvious changes were found in the levels of pAkt, tAkt, and tJNK. Ten differentially expressed genes were screened from HCCLM3-RFP xenograft tissues after treatment with IMOS at a dose of 90 mg/kg/d. Similar gene expression profiles were confirmed in HepG2 and Hep3B cells after treatment with 16 mg/mL IMOS. Conclusions:IMOS is a potential anti-HCC candidate through inhibition of ERK and JNK signaling.