論文 - 詳細
| RRC ID | 17604 |
|---|---|
| 著者 | Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, Giese N, O'Brien S, Yu A, Miller LL, Lannutti BJ, Burger JA. |
| タイトル | The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. |
| ジャーナル | Blood |
| Abstract |
In lymphocytes, the phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor-induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development. |
| 巻・号 | 118(13) |
| ページ | 3603-12 |
| 公開日 | 2011-9-29 |
| DOI | 10.1182/blood-2011-05-352492 |
| PII | S0006-4971(20)40454-9 |
| PMID | 21803855 |
| PMC | PMC4916562 |
| MeSH | Antineoplastic Agents / therapeutic use Cell Movement / drug effects Cell Survival / drug effects Cells, Cultured Chemokines / antagonists & inhibitors* Chemokines / metabolism Class I Phosphatidylinositol 3-Kinases Down-Regulation / drug effects Drug Evaluation, Preclinical Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy Leukemia, Lymphocytic, Chronic, B-Cell / metabolism Leukemia, Lymphocytic, Chronic, B-Cell / pathology* Metabolic Networks and Pathways / drug effects Metabolic Networks and Pathways / physiology Phosphoinositide-3 Kinase Inhibitors Purines / pharmacology* Purines / therapeutic use Quinazolinones / pharmacology* Quinazolinones / therapeutic use Receptors, Antigen, B-Cell / antagonists & inhibitors* Signal Transduction / drug effects |
| IF | 17.794 |
| 引用数 | 377 |
| WOS 分野 | HEMATOLOGY |
| 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 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 90 |
| 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 | KUSA-H1(RCB1990) 9-15C(RCB2323) TSt-4(RCB2116) |