Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells.
Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL and nontumoral accessory cells. CLL cells express CXCR4 chemokine receptors that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells constitutively secrete CXCL12, the ligand for CXCR4, thereby attracting and rescuing CLL B cells from apoptosis in a contact-dependent fashion. Therefore, the CXCR4-CXCL12 axis represents a potential therapeutic target in CLL. We evaluated the most active CXCR4-specific antagonists (T140, TC14012, TN14003) for their capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, chemotaxis, and migration of CLL cells beneath stromal cells. CXCL12-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was abolished by CXCR4 antagonists. TC14012 and TN14003 antagonized the antiapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists resensitized CLL cells cultured with stromal cells to fludarabine-induced apoptosis. These findings demonstrate that CXCR4 blocking agents effectively antagonize CXCL12-induced migratory and signaling responses and stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis. As such, small molecular CXCR4 antagonists may have activity in the treatment of patients with this disease.
Burger
Meike
M
Department of Medicine, Division of Hematology/Oncology, Freiburg University Hospital, Hugstetterstr 55, D-79106 Freiburg, Germany. burger@mm11.ukl.uni-freiburg.de
Hartmann
Tanja
T
Krome
Myriam
M
Rawluk
Justyna
J
Tamamura
Hirokazu
H
Fujii
Nobutaka
N
Kipps
Thomas J
TJ
Burger
Jan A
JA
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D009842:Oligopeptides; D010455:Peptides; D019718:Receptors, CXCR4; C504129:TC14012; C488289:TN14003; C116977:T140 peptide; D020928:Mitogen-Activated Protein Kinases; D014740:Vidarabine; C024352:fludarabine