| RRC ID |
60073
|
| 著者 |
Yoda H, Inoue T, Shinozaki Y, Lin J, Watanabe T, Koshikawa N, Takatori A, Nagase H.
|
| タイトル |
Direct Targeting of MYCN Gene Amplification by Site-Specific DNA Alkylation in Neuroblastoma.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Amplification of MYCN plays a pivotal role in multiple types of tumors and correlates with poor prognosis in high-risk neuroblastoma. Despite recent advances in the treatment of neuroblastoma, no approaches directly target the master oncogene MYCN. Difficulties in targeting the MYCN protein inspired us to develop a new gene-level-inhibitory strategy using a sequence-specific gene regulator. Here, we generated a MYCN-targeting pyrrole-imidazole (PI) polyamide, MYCN-A3, which directly binds to and alkylates DNA at homing motifs within the MYCN transcript. Pharmacologic suppression of MYCN inhibited the proliferation of cancer cells harboring MYCN amplification compared with MYCN nonamplified cancer cells. In neuroblastoma xenograft mouse models, MYCN-A3 specifically downregulated MYCN expression and suppressed tumor progression with no detectable adverse effects and resulted in prolonged overall survival. Moreover, treatment with MYCN-A3, but not MYCN nontargeting PI polyamide, precipitated a copy number reduction of MYCN in neuroblastoma cells with MYCN amplification. These findings suggest that directly targeting MYCN with MYCN-A3 is a novel therapeutic approach to reduce copy number of the MYCN gene for MYCN-amplified neuroblastoma. SIGNIFICANCE: This study presents a novel approach to drugging an amplified oncogene by showing that targeting gene amplification of MYCN suppresses MYCN expression and neuroblastoma growth.
|
| 巻・号 |
79(4)
|
| ページ |
830-840
|
| 公開日 |
2019-2-15
|
| DOI |
10.1158/0008-5472.CAN-18-1198
|
| PII |
0008-5472.CAN-18-1198
|
| PMID |
30584073
|
| MeSH |
Alkylation
Animals
Antineoplastic Agents, Alkylating / chemistry
Antineoplastic Agents, Alkylating / pharmacology*
Apoptosis
Biomarkers, Tumor / genetics
Cell Proliferation
Female
Gene Amplification / drug effects*
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Imidazoles / chemistry
Mice
Mice, Inbred BALB C
Mice, Nude
N-Myc Proto-Oncogene Protein / genetics*
Neuroblastoma / genetics*
Neuroblastoma / pathology
Neuroblastoma / prevention & control*
Nylons / chemistry
Nylons / pharmacology*
Pyrroles / chemistry
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
| IF |
8.378
|
| 引用数 |
5
|
| リソース情報 |
| ヒト・動物細胞 |
NB69(RCB0480) |
