RRC ID 44999
著者 Matsumoto T, Tabata K, Suzuki T.
タイトル The GANT61, a GLI inhibitor, induces caspase-independent apoptosis of SK-N-LO cells.
ジャーナル Biol Pharm Bull
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.
巻・号 37(4)
ページ 633-41
公開日 2014-1-1
DOI 10.1248/bpb.b13-00920
PII DN/JST.JSTAGE/bpb/b13-00920
PMID 24694609
MeSH Adaptor Proteins, Signal Transducing / metabolism Apoptosis / drug effects* Caspase 3 / metabolism Caspase 7 / metabolism Caspases / metabolism* Cell Cycle / drug effects Cell Line, Tumor Cyclin A / metabolism Enzyme Induction / drug effects* Humans Inhibitor of Apoptosis Proteins / metabolism Poly(ADP-ribose) Polymerases / metabolism Proto-Oncogene Proteins c-bcl-2 / biosynthesis Pyridines / pharmacology* Pyrimidines / pharmacology* Survivin Transcription Factors / antagonists & inhibitors* Transcription Factors / metabolism Tumor Suppressor Protein p53 / biosynthesis Zinc Finger Protein GLI1 rho GTP-Binding Proteins / biosynthesis
IF 1.863
引用数 14
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 LA-N-1(RCB0483) SK-N-SH(RCB0426)