| RRC ID |
61556
|
| 著者 |
Kashima H, Momose F, Umehara H, Miyoshi N, Ogo N, Muraoka D, Shiku H, Harada N, Asai A.
|
| タイトル |
Epirubicin, Identified Using a Novel Luciferase Reporter Assay for Foxp3 Inhibitors, Inhibits Regulatory T Cell Activity.
|
| ジャーナル |
PLoS One
|
| Abstract |
Forkhead box protein p3 (Foxp3) is crucial to the development and suppressor function of regulatory T cells (Tregs) that have a significant role in tumor-associated immune suppression. Development of small molecule inhibitors of Foxp3 function is therefore considered a promising strategy to enhance anti-tumor immunity. In this study, we developed a novel cell-based assay system in which the NF-κB luciferase reporter signal is suppressed by the co-expressed Foxp3 protein. Using this system, we screened our chemical library consisting of approximately 2,100 compounds and discovered that a cancer chemotherapeutic drug epirubicin restored the Foxp3-inhibited NF-κB activity in a concentration-dependent manner without influencing cell viability. Using immunoprecipitation assay in a Treg-like cell line Karpas-299, we found that epirubicin inhibited the interaction between Foxp3 and p65. In addition, epirubicin inhibited the suppressor function of murine Tregs and thereby improved effector T cell stimulation in vitro. Administration of low dose epirubicin into tumor-bearing mice modulated the function of immune cells at the tumor site and promoted their IFN-γ production without direct cytotoxicity. In summary, we identified the novel action of epirubicin as a Foxp3 inhibitor using a newly established luciferase-based cellular screen. Our work also demonstrated our screen system is useful in accelerating discovery of Foxp3 inhibitors.
|
| 巻・号 |
11(6)
|
| ページ |
e0156643
|
| 公開日 |
2016-1-1
|
| DOI |
10.1371/journal.pone.0156643
|
| PII |
PONE-D-16-09801
|
| PMID |
27284967
|
| PMC |
PMC4902191
|
| MeSH |
Animals
Antineoplastic Agents / isolation & purification*
Antineoplastic Agents / pharmacology
Cells, Cultured
Down-Regulation / drug effects
Drug Screening Assays, Antitumor / methods*
Epirubicin / isolation & purification*
Epirubicin / pharmacology
Female
Forkhead Transcription Factors / antagonists & inhibitors*
Genes, Reporter*
HEK293 Cells
Humans
Luciferases* / genetics
Luciferases* / metabolism
Lymphocyte Activation / drug effects
Mice
Mice, Inbred BALB C
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / immunology
|
| IF |
2.74
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637) |
