論文 - 詳細
| RRC ID | 67497 |
|---|---|
| 著者 | Gao F, Chen X, Lu J, Hu S, Xu H, Shi Y, Feng M, Ding J, Liu H, Luo C, Xie Z, Wang J. |
| タイトル | Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer. |
| ジャーナル | Eur J Med Chem |
| Abstract |
Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC50 ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo. |
| 巻・号 | 215 |
| ページ | 113274 |
| 公開日 | 2021-4-5 |
| DOI | 10.1016/j.ejmech.2021.113274 |
| PII | S0223-5234(21)00123-9 |
| PMID | 33592537 |
| MeSH | Animals Antineoplastic Agents / chemical synthesis Antineoplastic Agents / pharmacokinetics Antineoplastic Agents / therapeutic use* Apoptosis / drug effects Cell Line, Tumor Cell Proliferation / drug effects Ceramides / chemical synthesis Ceramides / pharmacokinetics Ceramides / therapeutic use* Drug Design Drug Synergism Female G1 Phase Cell Cycle Checkpoints / drug effects Heterocyclic Compounds, 3-Ring / therapeutic use* Humans Mice, Inbred BALB C Naphthalenes / chemical synthesis Naphthalenes / pharmacokinetics Naphthalenes / therapeutic use Neoplasms / drug therapy* Protein Kinase Inhibitors / chemical synthesis Protein Kinase Inhibitors / pharmacokinetics Protein Kinase Inhibitors / therapeutic use* Proto-Oncogene Proteins c-akt / antagonists & inhibitors* Reactive Oxygen Species / metabolism |
| IF | 5.573 |
| リソース情報 | |
| ヒト・動物細胞 | HGC-27(RCB0500) |