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题名: Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues
作者: Zhou, Zhixia1; Zhang, Cai1; null(夏成峰)3; Chen, Wenlan4, 5; Zhu, Huawei2; Shang, Pingping1; Ma, Fang1; Wang, Peng George4, 5; Zhang, Jian1; Xu, Wenfang2; Tian, Zhigang1, 6
刊名: MOLECULAR CANCER THERAPEUTICS
关键词: V-ALPHA-14I NKT CELLS ; KILLER T-CELLS ; IFN-GAMMA PRODUCTION ; ALPHA-GALACTOSYLCERAMIDE ; AUTOIMMUNE ENCEPHALOMYELITIS ; IMMUNE-RESPONSES ; DENDRITIC CELLS ; ACTIVATION ; BET ; GATA-3
英文摘要: Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1- or Th2-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3 or to further deoxylation on the terminal galactose to produce 4'"-dh-iGb3. Both modified iGb3, especially 4'"-dh-iGb3, stimulated more IFN-gamma production by hepatic NKT cells, and thus elicited preferential Th1 responses. Here, we found that 4'"-dh-iGb3-loaded bone marrow-derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared with unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4'"-dh-iGb3 stimulation increased STAT1 signaling by NKT cells, whereas the phosphorylation of Th2 type cytokine-associated transcription factor STAT6 signaling was not affected. Analysis of the structures of iGb3 and 4'"-dh-iGb3 revealed that 4'"-dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4'"-dh-iGb3 can improve the antitumor effects of a DC-based vaccine possibly by stabilizing the CD1d/glycolipid/TCR complex and stimulating IFN-gamma signaling of NKT cells. Furthermore, chemical modification of iGb3 can elicit Th1-biased responses by NKT cells, and 4'"-dh-iGb3 combined with a DC vaccine may serve as a potent new NKT-based therapy against tumors and infectious diseases. Mol Cancer Ther; 10(8); 1375-84. (C) 2011 AACR.
出版日期: 2011-08-01
卷号: 10, 期号:8, 页码:1375-1384
DOI标识: 10.1158/1535-7163.MCT-11-0030
语种: 英语
收录类别: SCI
学科分类: Oncology
ISSN号: 1535-7163
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.kib.ac.cn/handle/151853/5313
Appears in Collections:植物化学与西部植物资源持续利用国家重点实验室_期刊论文

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作者单位: 1.Shandong Univ, Inst Immunopharmacol & Immunotherapy, Sch Pharmaceut Sci, Jinan 250012, Peoples R China
2.Shandong Univ, Inst Med Chem, Sch Pharmaceut Sci, Jinan 250012, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Kunming, Peoples R China
4.Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA
5.Ohio State Univ, Dept Chem, Columbus, OH 43210 USA
6.Univ Sci & Technol China, Dept Microbiol & Immunol, Sch Life Sci, Hefei 230026, Peoples R China

Recommended Citation:
Zhou, ZX; Zhang, C; Xia, CF; Chen, WL; Zhu, HW; Shang, PP; Ma, F; Wang, PG; Zhang, J; Xu, WF; Tian, ZG.Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues,MOLECULAR CANCER THERAPEUTICS,2011,10(8):1375-1384
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