RRC ID |
45164
|
著者 |
El-Gamal D, Williams K, LaFollette TD, Cannon M, Blachly JS, Zhong Y, Woyach JA, Williams E, Awan FT, Jones J, Andritsos L, Maddocks K, Wu CH, Chen CS, Lehman A, Zhang X, Lapalombella R, Byrd JC.
|
タイトル |
PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL.
|
ジャーナル |
Blood
|
Abstract |
Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
|
巻・号 |
124(9)
|
ページ |
1481-91
|
公開日 |
2014-8-28
|
DOI |
10.1182/blood-2014-05-574830
|
PII |
S0006-4971(20)35576-2
|
PMID |
25001469
|
PMC |
PMC4148770
|
MeSH |
Apoptosis / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Protein Kinase C beta / antagonists & inhibitors*
Protein Kinase Inhibitors / therapeutic use*
Pyrroles / therapeutic use*
Quinazolines / therapeutic use*
Receptors, Antigen, B-Cell / metabolism
Tetradecanoylphorbol Acetate / pharmacology
Tumor Cells, Cultured
Tumor Microenvironment / drug effects
Wnt Signaling Pathway / drug effects
beta Catenin / metabolism
|
IF |
17.794
|
引用数 |
28
|
WOS 分野
|
HEMATOLOGY
|
リソース情報 |
ヒト・動物細胞 |
9-15C(RCB2323) |