AMD-3465

Chemokines, a subgroup of cytokines along with their receptors, are involved in various biologic processes and regulation of a wide range of immune responses in different physiologic and pathologic states such as tissue repair, infection, and inflammation. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled receptor (GPCR), has one identified natural ligand termed stromal-derived factor-1(SDF-1 or CXCL12). Evidence demonstrated that the ligation of SDF-1 to CXCR4 initiates several intracellular signaling pathways, regulating cell proliferation, survival, chemotaxis, migration, angiogenesis, adhesion, as well as bone marrow (BM)-resident cells homing and mobilization. Additionally, CXCR4 is expressed by tumor cells in blood malignancies and solid tumors. Therefore, CXCR4 is considered a potential therapeutic target in cancer therapy, and CXCR4 antagonists, including AMD3100, MSX-122, BPRCX807, WZ811, Motixafortide, TN14003, AMD3465, and AMD1170, have been employed in experimental and clinical studies to enhance cancer therapy. MSX-122 is a specific small-molecule antagonist of CXCR4/CXCL12 and the only orally available non-peptide CXCR4 antagonist with promising anti-cancer properties. Studies have shown that MSX-122 is particularly important in treating metastatic cancers and has great therapeutic potential. Accordingly, this review summarized the characteristics of MSX-122 and its effects on the CXCL12/CXCR4 axis as well as cancer therapy.

Diabetic osteoporosis (DOP) is a serious complication of diabetes, which brings a heavy burden to patients' families and society. The SDF-1/CXCR4 signal pathway may be a target to prevent articular cartilage degeneration. In this study, we studied the effects of high glucose (20 mmol/L) and CXCR4 antagonist AMD3465 (10 μmol/L) on the apoptosis and gene expression of osteoblast-like cells MG63 to determine a new treatment for DOP. CCK8 and clone formation assays confirmed that AMD3465 resisted the decrease of proliferation caused by high glucose. According to the results of scratch and transwell analysis, AMD3465 could remedy the decrease of cell migration and invasion induced by high glucose. The results of flow cytometry analysis and double staining with Hoechst and PI showed AMD3465 corrected the apoptosis induced by high glucose. In addition, high glucose regulated the expression of cell cycle- and apoptosis-related proteins, while AMD3465 blocked the regulation of high glucose. Furthermore, high glucose enhanced the expression levels of SDF-1 and CXCR4 in MG63 cells, as well as the release of MMP1, 3, 9 and 13. AMD3465 inhibited the release of MMPs. The results showed that AMD3465 resisted the apoptosis of MG63 cells induced by high glucose, provided a new strategy for the therapy of DOP.