CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth

Exp Hematol. 2011 Mar;39(3):282-92. doi: 10.1016/j.exphem.2010.11.010. Epub 2010 Dec 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / pharmacology
  • Antineoplastic Agents
  • Apoptosis / drug effects*
  • Benzylamines
  • Chemokine CXCL12 / metabolism
  • Cyclams
  • HL-60 Cells
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Jurkat Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Mice
  • Mice, SCID
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Neoplasm Transplantation
  • Peptides / pharmacology*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism


  • 4-fluorobenzoyl-TN-14003
  • Anti-HIV Agents
  • Antineoplastic Agents
  • Benzylamines
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Cyclams
  • Heterocyclic Compounds
  • Peptides
  • Receptors, CXCR4
  • plerixafor