論文 - 詳細
| RRC ID | 78601 |
|---|---|
| 著者 | Deguchi A, Watanabe-Takahashi M, Mishima T, Omori T, Ohto U, Arashiki N, Nakamura F, Nishikawa K, Maru Y. |
| タイトル | Novel multivalent S100A8 inhibitory peptides attenuate tumor progression and metastasis by inhibiting the TLR4-dependent pathway. |
| ジャーナル | Cancer Gene Ther |
| Abstract |
The tumor-elicited inflammation is closely related to tumor microenvironment during tumor progression. S100A8, an endogenous ligand of Toll-like receptor 4 (TLR4), is known as a key molecule in the tumor microenvironment and premetastatic niche formation. We firstly generated a novel multivalent S100A8 competitive inhibitory peptide (divalent peptide3A5) against TLR4/MD-2, using the alanine scanning. Divalent peptide3A5 suppressed S100A8-mediated interleukin-8 and vascular endothelial growth factor production in human colorectal tumor SW480 cells. Using SW480-transplanted xenograft models, divalent peptide3A5 suppressed tumor progression in a dose-dependent manner. We demonstrated that combination therapy with divalent peptide3A5 and bevacizumab synergistically suppressed tumor growth in SW480 xenograft models. Using syngeneic mouse models, we found that divalent peptide3A5 improved the efficacy of anti-programmed death (PD)1 antibody, and lung metastasis. In addition, by using multivalent peptide library screening based on peptide3A5, we then isolated two more candidates; divalent ILVIK, and tetravalent ILVIK. Of note, multivalent ILVIK, but not monovalent ILVIK showed competitive inhibitory activity against TLR4/MD-2 complex, and anti-tumoral activity in SW480 xenograft models. As most tumor cells including SW480 cells also express TLR4, S100A8 inhibitory peptides would target both the tumor microenvironment and tumor cells. Thus, multivalent S100A8 inhibitory peptides would provide new pharmaceutical options for aggressive cancers. |
| 巻・号 | 30(7) |
| ページ | 973-984 |
| 公開日 | 2023-7-1 |
| DOI | 10.1038/s41417-023-00604-3 |
| PII | 10.1038/s41417-023-00604-3 |
| PMID | 36932197 |
| PMC | PMC10021052 |
| MeSH | Animals Calgranulin A / metabolism Calgranulin B* / metabolism Humans Mice Peptides / metabolism Peptides / pharmacology Toll-Like Receptor 4* Vascular Endothelial Growth Factor A / metabolism |
| IF | 4.534 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LLC(RCB0558) |