GANT61

Hedgehog通路抑制剂；抑制GLI

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产品号 #（选择产品）

产品号 #73692_C

Hedgehog通路抑制剂；抑制GLI

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总览

GANT61是一种六氢嘧啶衍生物，可选择性抑制Hedgehog信号通路中的GLI转录因子。GANT61作用于Smoothened的下游，通过阻止GLI1和GLI2的DNA结合来抑制其介导的转录（在GLI转染细胞系中，IC₅₀=5 μM）（Lauth et al.）。

癌症研究
·抑制GLI1水平升高的癌细胞系（PANC1和22Rv1）的体外增殖，并阻止小鼠22Rv1肿瘤的发展（Lauth et al.）。
·抑制体外和小鼠异种移植模型中的胰腺癌干细胞生长（Fu et al.）。
·通过抑制DNA复制，以Caspase非依赖的方式诱导原始神经外胚层肿瘤细胞系的细胞死亡（Matsumoto et al.）。
·导致髓系白血病细胞凋亡，并且在某些细胞系中与雷帕霉素搭配使用时效果更佳（Pan et al.）。

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Product Information Sheet

Product Name

GANT61

Catalog #

73692

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All

Language

English

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Safety Data Sheet

Product Name

GANT61

Catalog #

73692

Lot #

All

Language

English

Abstract

GANT61 is a small-molecule inhibitor of glioma-associated oncogene 1 (GLI1)- and GLI2-mediated transcription at the nuclear level that exerts its effect by preventing DNA binding. It has been demonstrated to induce cell death against Ewing's sarcoma family tumor (ESFT) cell lines in a dose-dependent manner. The most sensitive cell line was SK-N-LO, which expresses the EWS-FLI1 fusion gene. SK-N-LO cells treated with GANT61 showed cellular and nuclear morphological changes, including cell shrinkage, chromatin condensation and nuclear fragmentation, in a concentration-dependent manner, as visualized by Hoechst 33342 staining. Furthermore, annexin V-propidium iodide (PI) double-staining revealed a significant increase in the number of late apoptotic cells. GANT61 induced a significant decrease in the proportion of cells in the S phase. Significant decrease of the protein levels of GLI2, survivin, cyclin A and claspin, and significant increase of p21 expression was also observed in the cells treated with GANT61. Moreover, poly (ADP-ribose) polymerase (PARP) cleavage was observed, but no cleavage of caspase-3 or -7, or any change in the expressions of Bcl-2 or p53 were observed. These findings suggest that GANT61 induces cell death of SK-N-LO cells in a caspase-independent manner, by inhibiting DNA replication in the S phase.

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GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Fu J et al. Cancer letters 2013 MAR

Abstract

Multiple lines of evidence suggest that the Sonic Hedgehog (Shh) signaling pathway is aberrantly reactivated in pancreatic cancer stem cells (CSCs). The objectives of this study were to examine the molecular mechanisms by which GANT-61 (Gli transcription factor inhibitor) regulates stem cell characteristics and tumor growth. Effects of GANT-61 on CSC's viability, spheroid formation, apoptosis, DNA-binding and transcriptional activities, and epithelial-mesenchymal transition (EMT) were measured. Humanized NOD/SCID/IL2R gamma(null) mice were used to examine the effects of GANT-61 on CSC's tumor growth. GANT-61 inhibited cell viability, spheroid formation, and Gli-DNA binding and transcriptional activities, and induced apoptosis by activation of caspase-3 and cleavage of Poly-ADP ribose Polymerase (PARP). GANT-61 increased the expression of TRAIL-R1/DR4, TRAIL-R2/DR5 and Fas, and decreased expression of PDGFRα and Bcl-2. GANT-61 also suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. In addition, GANT-61 inhibited pluripotency maintaining factors Nanog, Oct4, Sox-2 and cMyc. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GANT-61-treated pancreatic CSCs. Furthermore, GANT-61 inhibited CSC tumor growth which was associated with up-regulation of DR4 and DR5 expression, and suppression of Gli1, Gli2, Bcl-2, CCND2 and Zeb1 expression in tumor tissues derived from NOD/SCID IL2Rγ null mice. Our data highlight the importance of Shh pathway for self-renewal and metastasis of pancreatic CSCs, and also suggest Gli as a therapeutic target for pancreatic cancer in eliminating CSCs.

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Gli inhibitor GANT61 causes apoptosis in myeloid leukemia cells and acts in synergy with rapamycin. Pan D et al. Leukemia research 2012 JUN

Abstract

Aberrant reactivation of Gli signaling has been described in a wide variety of human cancers and rapamycin can down-regulate Gli pathway in some solid tumors. In this study, we attempt to define the cytotoxic effect of Gli inhibitor on AML cells. And the regulation action of rapamycin on Gli in AML cells also has been assessed. Gli inhibitor GANT61 caused growth arrest and apoptosis in AML cells. Rapamycin decreased not only the Gli protein and mRNA expressions but also expression of the Gli-luciferase reporter in AML cells. Synergism effect between GANT61 and rapamycin was found in Kasumi-1, HL-60 and U937 cell lines. The results suggest that aberrant Gli activation is a feature of some myeloid leukemic cells and Gli activiation can be down-regulated by rapamycin.

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