期刊
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN
卷 95, 期 4, 页码 693-699出版社
CHEMICAL SOC JAPAN
DOI: 10.1246/bcsj.20210453
关键词
Cancer stem cells; Transcription; Pyrrole-imidazole polyamide
资金
- AMED [JP20am0101101]
- Platform Project for Supporting Drug Discovery and Life Science Research [BINDS] [20H05936]
- Takeda Science Foundation [16H06356]
- MEXT fellowship
- NIH [R01CA236350]
Research suggests that targeting Gli-mediated transcription to inhibit the proliferation of cancer stem cells may be a promising strategy.
Cancer stem cells (CSCs) are a small subpopulation of cells within the cancer tissue that play major roles in metastasis, drug resistance, and recurrence. Synthetic ligands capable of recognizing the specific DNA sequences are believed to be promising in targeted disruption of transcription factor-DNA interaction, which can achieve regulatory control over tumorsusceptible signaling pathways. Herein, we report a sequence-specific cyclic pyrrole-imidazole polyamide capable of targeting Gli-mediated transcription and inhibiting the hedgehog pathway which is implied to play a major role in cancer stem cell proliferation. The DNA binding affinities of cyclic polyamides were superior to corresponding hairpin polyamides. Mechanistically, the cyclic PIPs blocked the Gli function, which was confirmed by qRT-PCR and luciferase assay. Furthermore, combinatorial treatment of cyclic PIPs and temozolomide (TMZ) to glioblastoma and brain cancer stem cells showed increased cell death compared to TMZ alone. Taken together, cyclic PIPs targeting Gli-mediated transcription can be a promising strategy in suppressing the CSCs.
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