論文 - 詳細
| RRC ID | 68808 |
|---|---|
| 著者 | Ota Y, Yoda H, Inoue T, Watanabe T, Shinozaki Y, Takatori A, Nagase H. |
| タイトル | Targeting anaplastic lymphoma kinase (ALK) gene alterations in neuroblastoma by using alkylating pyrrole-imidazole polyamides. |
| ジャーナル | PLoS One |
| Abstract |
Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance. |
| 巻・号 | 16(9) |
| ページ | e0257718 |
| 公開日 | 2021-1-1 |
| DOI | 10.1371/journal.pone.0257718 |
| PII | PONE-D-20-38161 |
| PMID | 34591871 |
| PMC | PMC8483358 |
| MeSH | Anaplastic Lymphoma Kinase / genetics* Anaplastic Lymphoma Kinase / metabolism* Animals Antineoplastic Agents / administration & dosage* Antineoplastic Agents / chemical synthesis Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Down-Regulation Drug Resistance, Neoplasm / drug effects* Female Gene Expression Regulation, Neoplastic / drug effects Humans Imidazoles / administration & dosage* Imidazoles / chemical synthesis Imidazoles / chemistry Imidazoles / pharmacology Mice Mutation Neuroblastoma / drug therapy* Neuroblastoma / genetics Neuroblastoma / metabolism Nylons / chemical synthesis Nylons / chemistry Phosphorylation / drug effects Pyrroles / chemistry* Xenograft Model Antitumor Assays |
| IF | 2.74 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 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 | Ba/F3-CL1(RCB4474) |