Hematopoietic and epithelial
cancer cells express CXCR4, a seven-transmembrane
G-protein-coupled
chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the
ligand for CXCR4. Activation of CXCR4 induces
leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains
leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as
Plerixafor (
AMD3100) and
T140 analogs, can disrupt adhesive
tumor-stroma interactions and mobilize
leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in
leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce
leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between
leukemia cells (and a variety of other
tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on
leukemia and other
cancers.