Hatse Sigrid, Princen Katrien, Bridger Gary, De Clercq Erik, Schols Dominique
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
FEBS Lett. 2002 Sep 11;527(1-3):255-62. doi: 10.1016/s0014-5793(02)03143-5.
This study was undertaken to demonstrate the unique specificity of the chemokine receptor CXCR4 antagonist AMD3100. Calcium flux assays with selected chemokine/cell combinations, affording distinct chemokine receptor specificities, revealed no interaction of AMD3100 with any of the chemokine receptors CXCR1 through CXCR3, or CCR1 through CCR9. In contrast, AMD3100 potently inhibited CXCR4-mediated calcium signaling and chemotaxis in a concentration-dependent manner in different cell types. Also, AMD3100 inhibited stromal cell-derived factor (SDF)-1-induced endocytosis of CXCR4, but did not affect phorbol ester-induced receptor internalization. Importantly, AMD3100 by itself was unable to elicit intracellular calcium fluxes, to induce chemotaxis, or to trigger CXCR4 internalization, indicating that the compound does not act as a CXCR4 agonist. Specific small-molecule CXCR4 antagonists such as AMD3100 may play an important role in the treatment of human immunodeficiency virus infections and many other pathological processes that are dependent on SDF-1/CXCR4 interactions (e.g. rheumatoid arthritis, atherosclerosis, asthma and breast cancer metastasis).
本研究旨在证明趋化因子受体CXCR4拮抗剂AMD3100的独特特异性。采用具有不同趋化因子受体特异性的特定趋化因子/细胞组合进行钙流测定，结果显示AMD3100与任何趋化因子受体CXCR1至CXCR3或CCR1至CCR9均无相互作用。相反，AMD3100在不同细胞类型中以浓度依赖的方式有效抑制CXCR4介导的钙信号传导和趋化作用。此外，AMD3100抑制基质细胞衍生因子（SDF）-1诱导的CXCR4内吞作用，但不影响佛波酯诱导的受体内化。重要的是，AMD3100自身无法引发细胞内钙流、诱导趋化作用或触发CXCR4内化，这表明该化合物并非作为CXCR4激动剂发挥作用。特异性小分子CXCR4拮抗剂如AMD3100可能在治疗人类免疫缺陷病毒感染以及许多其他依赖SDF-1/CXCR4相互作用的病理过程（如类风湿性关节炎、动脉粥样硬化、哮喘和乳腺癌转移）中发挥重要作用。
