RRC ID 68568
Author Fiorcari S, Brown WS, McIntyre BW, Estrov Z, Maffei R, O'Brien S, Sivina M, Hoellenriegel J, Wierda WG, Keating MJ, Ding W, Kay NE, Lannutti BJ, Marasca R, Burger JA.
Title The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells.
Journal PLoS One
Abstract CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNFα-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood.
Volume 8(12)
Pages e83830
Published 2013-1-1
DOI 10.1371/journal.pone.0083830
PII PONE-D-13-27505
PMID 24376763
PMC PMC3871531
MeSH Animals Bone Marrow Cells / pathology* Cell Adhesion / drug effects Cell Line, Tumor Cell Survival / drug effects Endothelial Cells / drug effects Endothelial Cells / pathology* Enzyme Inhibitors / pharmacology* Gene Expression Regulation, Neoplastic / drug effects Integrin alpha4beta1 / metabolism Integrins / metabolism* Leukemia, Lymphocytic, Chronic, B-Cell / pathology* Mice Phosphoinositide-3 Kinase Inhibitors* Purines / pharmacology* Quinazolinones / pharmacology* Signal Transduction / drug effects Stromal Cells / drug effects Stromal Cells / pathology Vascular Cell Adhesion Molecule-1 / metabolism
IF 2.74
Human and Animal Cells KUSA-H1(RCB1990) 9-15C(RCB2323) UV♀2(RCB1994) StromaNKtert(RCB2350)