論文 - 詳細
| RRC ID | 65428 |
|---|---|
| 著者 | Chan-On W, Huyen NT, Songtawee N, Suwanjang W, Prachayasittikul S, Prachayasittikul V. |
| タイトル | Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells. |
| ジャーナル | Drug Des Devel Ther |
| Abstract |
PURPOSE:Fork head box M1 (FoxM1) is an oncogenic transcription factor frequently elevated in numerous cancers, including cholangiocarcinoma (CCA). A growing body of evidence documents its diverse functions contributing to tumorigenesis and cancer progression. As such, discovery of agents that can target FoxM1 would be valuable for the treatment of CCA. The quinoline-based compounds, namely clioquinol (CQ) and nitroxoline (NQ), represent a new class of anticancer drug. However, their efficacy and underlying mechanisms have not been elucidated in CCA. In this study, anticancer activities and inhibitory effects of CQ and NQ on FoxM1 signaling were explored using CCA cells. METHODS:The effects of CQ and NQ on cell viability and proliferation were evaluated using the colorimetric 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazolium (MTS assay). Colony formation and cell migration affected by CQ and NQ were investigated using a clonogenic and a wound healing assay, respectively. To demonstrate the agents' effects on FoxM1 signaling, expression levels of the target genes were quantitatively determined using real-time polymerase chain reaction. RESULTS:CQ and NQ significantly inhibited cell survival of HuCCT1 and Huh28 in a dose- and a time-dependent fashion. Further investigations using the rapidly proliferating HuCCT1 cells revealed significant suppression of cell proliferation and colony formation induced by low doses of the compounds. Treatment of CQ and NQ repressed expression of cyclin D1 but enhanced expression of p21. Most importantly, upon CQ and NQ treatment, expression of oncogenic FoxM1 was markedly decreased concomitant with downregulation of various FoxM1's downstream targets including cdc25b, CENP-B, and survivin. In addition, the compounds distinctly impaired HuCCT1 migration as well as inhibited expression of matrix metalloproteinase (MMP)-2 and MMP-9. CONCLUSION:Collectively, this study reports for the first time the anticancer effects of CQ and NQ against CCA cells, and highlights new insights into the mechanism of actions of the quinoline-based compounds to disrupt FoxM1 signaling. |
| 巻・号 | 9 |
| ページ | 2033-47 |
| 公開日 | 2015-1-1 |
| DOI | 10.2147/DDDT.S79313 |
| PII | dddt-9-2033 |
| PMID | 25897210 |
| PMC | PMC4396583 |
| MeSH | Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Bile Duct Neoplasms / drug therapy* Bile Duct Neoplasms / pathology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / pathology Clioquinol / chemistry Clioquinol / pharmacology* Dose-Response Relationship, Drug Down-Regulation / drug effects Drug Screening Assays, Antitumor Forkhead Box Protein M1 Forkhead Transcription Factors / antagonists & inhibitors* Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism Humans Models, Molecular Molecular Structure Nitroquinolines / chemistry Nitroquinolines / pharmacology* Quinolines / chemistry* Signal Transduction / drug effects Structure-Activity Relationship Time Factors |
| IF | 3.216 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) HuH-28(RCB1943) |