Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells
Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells
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DOI：
10.1182/blood-2004-12-4918
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发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Burger, JA
中科院分区：
文献类型：
--
作者：
Burger, M;Hartmann, T;Burger, JA
慢性淋巴细胞白血病（CLL） B细胞的生长和存活受CLL与非肿瘤辅助细胞相互作用的影响。CLL细胞表达CXCR4趋化因子受体，指导白血病细胞趋化。骨髓基质细胞或乳样细胞组成性地分泌CXCL12， CXCR4的配体，从而以接触依赖的方式吸引和挽救CLL B细胞凋亡。因此，CXCR4-CXCL12轴代表了CLL的潜在治疗靶点。我们评估了最活跃的cxcr4特异性拮抗剂（T140, TC14012, TN14003）在CLL细胞中抑制CXCL12反应的能力。T140或其类似物抑制肌动蛋白聚合、趋化性和CLL细胞在基质细胞下的迁移。cxcl12诱导的p44/42丝裂原活化蛋白激酶（MAPK）和转录信号换能器和激活因子3 （STAT3）的磷酸化被CXCR4拮抗剂消除。TC14012和TN14003可拮抗合成CXCL12的抗凋亡作用和基质细胞介导的CLL细胞自发凋亡保护作用。此外，我们发现基质细胞保护CLL细胞免受化疗诱导的凋亡。CXCR4拮抗剂治疗使基质细胞培养的CLL细胞对氟达拉滨诱导的凋亡重敏。这些发现表明，CXCR4阻滞剂可以有效地拮抗cxcl12诱导的迁移和信号反应，并保护CLL细胞免受自发或氟达拉滨诱导的凋亡。因此，小分子CXCR4拮抗剂可能在治疗这种疾病的患者中具有活性。
Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL and nontumoral accessory cells. CLL cells express CXCR4 chemokine receptors that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells constitutively secrete CXCL12, the ligand for CXCR4, thereby attracting and rescuing CLL B cells from apoptosis in a contact-dependent fashion. Therefore, the CXCR4-CXCL12 axis represents a potential therapeutic target in CLL. We evaluated the most active CXCR4-specific antagonists (T140, TC14012, TN14003) for their capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, chemotaxis, and migration of CLL cells beneath stromal cells. CXCL12-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was abolished by CXCR4 antagonists. TC14012 and TN14003 antagonized the antlapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists resensitized CLL cells cultured with stromal cells to fludarabine-induced apoptosis. These findings demonstrate that CXCR4 blocking agents effectively antagonize CXCL12-induced migratory and signaling responses and stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis. As such, small molecular CXCR4 antagonists may have activity in the treatment of patients with this disease.