Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Blood. 2012 Feb 16;119(7):1717-25. doi: 10.1182/blood-2011-04-347518. Epub 2011 Dec 20.
The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.
趋化因子受体 CXCR4 通常调节骨髓基质干细胞的相互作用，在多种恶性血液病细胞（包括淋巴瘤和淋巴细胞白血病）中高度表达。一种新的治疗概念已经出现，即 CXCR4 可能成为化疗和免疫治疗治疗血液病肿瘤的辅助治疗的有效治疗靶点。在本研究中，我们开发了趋化因子受体 CXCR4 的穿透性脂肽拮抗剂 pepducins，以阻断 CXCL12-CXCR4 跨膜信号转导至细胞内 G 蛋白。我们证明，针对 CXCR4 的第一（i1）或第三（i3）细胞内环的 pepducins 完全阻断了淋巴细胞白血病和淋巴瘤的 CXCL12 介导的细胞迁移。基质细胞共培养可保护淋巴瘤细胞免受针对 CD20 的 Ab 利妥昔单抗治疗的凋亡。然而，CXCR4 pepducins 与利妥昔单抗联合治疗可显著增加利妥昔单抗的凋亡作用。此外，用 pepducins 单独或联合利妥昔单抗治疗携带弥散性淋巴瘤异种移植物的小鼠显著增加了它们的存活。这些数据表明，趋化因子受体 CXCR4 的信号可以被穿透性 pepducins 有效抑制，这代表了治疗淋巴样恶性肿瘤的一种新的潜在治疗策略。
