CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth.
OBJECTIVE
The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis.


METHODS
Here, we demonstrate that the CXCR4 antagonist, 4F-benzoyl-TN14003 (BKT140), but not AMD3100, exhibits a CXCR4-dependent preferential cytotoxicity toward malignant cells of hematopoietic origin. BKT140 significantly and preferentially stimulated multiple myeloma apoptotic cell death. BKT140 treatment induced morphological changes, phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 arrest, and DNA double-stranded breaks.


RESULTS
In vivo, subcutaneous injections of BKT140 significantly reduced, in a dose-dependent manner, the growth of human acute myeloid leukemia and multiple myeloma xenografts. Tumors from animals treated with BKT140 were smaller in size and weights, had larger necrotic areas and high apoptotic scores.


CONCLUSIONS
Taken together, these results suggest a potential therapeutic use for BKT140 in multiple myeloma and leukemia patients.
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Katia
K
Beider
Michal
M
Begin
Michal
M
Abraham
Hanna
H
Wald
Ido D
ID
Weiss
Ori
O
Wald
Eli
E
Pikarsky
Evelyne
E
Zeira
Orly
O
Eizenberg
Eithan
E
Galun
Izhar
I
Hardan
Dan
D
Engelhard
Arnon
A
Nagler
Amnon
A
Peled
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D018922:HL-60 Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009368:Neoplasm Transplantation; D010455:Peptides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C477728:4-fluorobenzoyl-TN-14003; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010455:Peptides; D019718:Receptors, CXCR4; C088327:plerixafor