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. Materials and 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.
Bibliographical noteFunding Information:
We thank Mery Clausen (Gene Therapy Institute, Hadassah Hospital) for technical assistance. We wish to thank the Naor family for their support memorizing their dear son-in-law, Mr. Guy Weinshtock, with the Guy Weinshtock Multiple Myeloma Foundation, which supports research in the field of MM at the Division of Hematology at Chaim Sheba Medical Center (Tel Hashomer, Israel) and the Jacqueline Seroussi Grant Award (to A.N.). This work was supported in part by a grant from Biokine Therapeutics Ltd . (Ness Ziona, Israel).