Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
J Thorac Cardiovasc Surg. 2012 Nov;144(5):1167-1175.e1. doi: 10.1016/j.jtcvs.2012.07.031. Epub 2012 Aug 24.
CXCR4/CXCL12 interactions promote non-small cell lung cancer (NSCLC) growth and dissemination. Furthermore, this axis might promote NSCLC resistance to chemotherapy and/or radiotherapy. Therefore, the CXCR4/CXCL12 axis constitutes an attractive therapeutic target for the treatment of NSCLC. We aimed to characterize the therapeutic efficacy of the novel CXCR4 antagonist BKT140 against human NSCLC.
We determined the CXCR4 expression in 5 NSCLC cell lines (H358, A549, H460, H1299, and L4). We then tested the colony-forming capacity and proliferation of these cells in the presence of CXCL12 and BKT140. Next, we measured the in vivo growth of A549 and H460 xenografts with or without BKT140 treatment. Finally, we examined, in vitro, the potential antiproliferative effect of BKT140 combined with cisplatin or paclitaxel and after irradiation of NSCLC cells.
All tested cell lines expressed CXCR4 and showed increased colony formation in response to CXCL12 stimulation. BKT140 reduced the colony-forming capacity of NSCLC cells. Proliferation assays demonstrated both cytotoxic and cytostatic properties for this peptide. H460 cells were the most sensitive to BKT140 and A549 cells the least. Subcutaneous administration of BKT140 significantly delayed the development of H460 xenografts and showed a similar trend for A549 xenografts. Finally, the antiproliferative effects of BKT140 appears to be additive to those of chemotherapeutic drugs and radiotherapy.
Targeting the CXCL12/CXCR4 axis with BKT140 attenuated NSCLC cells tumor growth and augmented the effects of chemotherapy and radiotherapy. Future research will benefit from delineating the downstream mechanism of BKT140 action and defining BKT140 susceptibility markers.
趋化因子受体 4（CXCR4）/趋化因子配体 12（CXCL12）相互作用促进非小细胞肺癌（NSCLC）的生长和扩散。此外，该轴可能促进 NSCLC 对化疗和/或放疗的耐药性。因此，CXCR4/CXCL12 轴是治疗 NSCLC 的一个有吸引力的治疗靶点。我们旨在描述新型 CXCR4 拮抗剂 BKT140 对人 NSCLC 的治疗效果。
我们确定了 5 种 NSCLC 细胞系（H358、A549、H460、H1299 和 L4）中的 CXCR4 表达。然后，我们在 CXCL12 和 BKT140 的存在下测试了这些细胞的集落形成能力和增殖。接下来，我们测量了有无 BKT140 治疗的 A549 和 H460 异种移植瘤的体内生长情况。最后，我们在体外研究了 BKT140 与顺铂或紫杉醇联合以及 NSCLC 细胞照射后的潜在抗增殖作用。
所有测试的细胞系均表达 CXCR4，并在 CXCL12 刺激下表现出增加的集落形成。BKT140 降低了 NSCLC 细胞的集落形成能力。增殖试验表明该肽具有细胞毒性和细胞抑制作用。H460 细胞对 BKT140 最敏感，A549 细胞最不敏感。BKT140 的皮下给药显著延迟了 H460 异种移植瘤的发展，并显示出对 A549 异种移植瘤的类似趋势。最后，BKT140 的抗增殖作用似乎与化疗药物和放疗的作用相加。
用 BKT140 靶向 CXCL12/CXCR4 轴可减弱 NSCLC 细胞的肿瘤生长，并增强化疗和放疗的效果。未来的研究将受益于描绘 BKT140 作用的下游机制和确定 BKT140 敏感性标志物。
