Targeting Chemokine Receptor CXCR4 for Treatment of HIV-1 Infection, Tumor Progression, and Metastasis

Abstract

The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and for the development and dissemination of various types of cancers, including gastrointestinal, cutaneous, head and neck, pulmonary, gynecological, genitourinary, neurological, and hematological malignancies. The T-cell (T)-tropic HIV-1 strains use CXCR4 as the entry coreceptor; consequently, multiple CXCR4 antagonistic inhibitors have been developed for the treatment of acquired immune deficiency syndrome (AIDS). However, other potential applications of CXCR4 antagonists have become apparent since its discovery in 1996. In fact, increasing evidence demonstrates that epithelial and hematopoietic tumor cells exploit the interaction between CXCR4 and its natural ligand, stromal cell-derived factor (SDF)-1α, which normally regulates leukocyte migration. The CXCR4 and/or SDF-1α expression patterns in tumor cells also determine the sites of metastatic spread. In addition, the activation of CXCR4 by SDF-1α promotes invasion and proliferation of tumor cells, enhances tumor-associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane. As such, the evaluation of CXCR4 and/or SDF-1α expression levels has a significant prognostic value in various types of malignancies. Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy.

EGFR expression is associated with cytoplasmic staining of CXCR4 and predicts poor prognosis in triple-negative breast carcinomas

“…After 6 h, cells were supplied with 3 ml/well RPMI-1640 supplemented with 10% FBS. Selection commenced at 48 h following infection; shCXCR4 cells were treated with 2 µg/ml puromycin (Sangon Biotech, Shanghai, China) and shEGFR cells were treated with 1,000 µg/ml geneticin (G418; Sangon Biotech) (3). The cells that were infected with shRNAs targeting CXCR4 and EGFR were selected with puromycin or G418 simultaneously for ~2 weeks.…”

“…In the past two decades, C-X-C motif chemokine receptor type 4 (CXCR4) has been identified to be important in cancer metastasis (3). Chemokines belong to a superfamily of small, cytokine-like proteins that induce cytoskeletal rearrangement and adhesion to endothelial cells, and direct migration through their interaction with G-protein-coupled receptors (GPCRs).…”

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

“…In addition, over-expression of CXCR4 has been demonstrated to promote metastasis and associate with unfavorable prognosis in breast and lung cancer [27, 28]. Although CXCR4 has been reported to be relevant with various tumor progress and metastasis [29], the detailed molecular mechanisms of CXCR4 on osteosarcoma were still obscure.…”

Design, synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4

“…CXCR4 transmits signals from extracellular ligands to intracellular biological pathways upon binding with its natural ligand, stromal-cell derived factor (SDF)-1α [4–6]. The SDF-1α-CXCR4 axis plays an important role in the regulation of leukocyte chemotaxis, angiogenesis, cancer metastasis, and HIV-1 infection [7–11]. …”