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.
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 humanacute 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 leukemiapatients.
Authors: Darja Karpova; Julie K Ritchey; Matthew S Holt; Grazia Abou-Ezzi; Darlene Monlish; Lena Batoon; Susan Millard; Gabriele Spohn; Eliza Wiercinska; Ezhil Chendamarai; Wei Yang; Stephanie Christ; Leah Gehrs; Laura G Schuettpelz; Klaus Dembowsky; Allison R Pettit; Michael P Rettig; Halvard Bonig; John F DiPersio Journal: Blood Date: 2017-04-11 Impact factor: 22.113
Authors: M Abraham; S Klein; B Bulvik; H Wald; I D Weiss; D Olam; L Weiss; K Beider; O Eizenberg; O Wald; E Galun; A Avigdor; O Benjamini; A Nagler; Y Pereg; S Tavor; A Peled Journal: Leukemia Date: 2017-03-10 Impact factor: 11.528
Authors: Orit Jacobson; Ido D Weiss; Lawrence P Szajek; Gang Niu; Ying Ma; Dale O Kiesewetter; Joshua M Farber; Xiaoyuan Chen Journal: Theranostics Date: 2011-04-19 Impact factor: 11.556
Authors: Francoise Bachelerie; Adit Ben-Baruch; Amanda M Burkhardt; Christophe Combadiere; Joshua M Farber; Gerard J Graham; Richard Horuk; Alexander Hovard Sparre-Ulrich; Massimo Locati; Andrew D Luster; Alberto Mantovani; Kouji Matsushima; Philip M Murphy; Robert Nibbs; Hisayuki Nomiyama; Christine A Power; Amanda E I Proudfoot; Mette M Rosenkilde; Antal Rot; Silvano Sozzani; Marcus Thelen; Osamu Yoshie; Albert Zlotnik Journal: Pharmacol Rev Date: 2013-11-11 Impact factor: 25.468