Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia
Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia
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DOI：
10.1182/blood-2011-04-347518
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发表时间：
2012-02-16
期刊：
影响因子：
20.3
通讯作者：
Covic, Lidija
中科院分区：
文献类型：
--
作者：
O'Callaghan, Katie;Lee, Lydia;Covic, Lidija
趋化因子受体CXCR 4通常调节骨髓中的基质干细胞相互作用，在多种恶性血液细胞上高度表达，包括淋巴瘤和淋巴细胞性白血病。已经出现了一种新的治疗概念，其中CXCR 4可能是一种有效的治疗靶点，作为化疗和免疫疗法治疗血液肿瘤的辅助手段。在本研究中，我们开发了肽蛋白，CXCR 4的细胞穿透脂肽拮抗剂，阻断CXCL 12-CXCR 4跨膜信号转导到细胞内G蛋白。我们证明，靶向CXCR 4的第一（i1）或第三（i3）细胞内环的肽蛋白完全消除了CXCL 12介导的淋巴细胞白血病和淋巴瘤细胞迁移。间质细胞共培养保护淋巴瘤细胞在CD 20靶向抗体利妥昔单抗治疗后免于凋亡。然而，CXCR 4肽蛋白和利妥昔单抗的组合治疗显著增加利妥昔单抗的凋亡作用。此外，用单独的pepducins或与利妥昔单抗联合治疗携带播散性淋巴瘤异种移植物的小鼠显著增加了它们的存活率。这些数据表明，CXCL 12-CXCR 4信号可以有效地抑制细胞穿透肽，这代表了一个潜在的新的淋巴恶性肿瘤的治疗策略。（Blood.2012;119（7）：1717-1725）
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-targetedAb 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. (Blood.2012;119(7):1717-1725)