Kim Ji-Hea, Lee Seung-Jin, Kang Ka-Won, Lee Byung-Hyun, Park Yong, Kim Byung-Soo
Institute of Stem Cell Research, Korea University College of Medicine, Seoul, South Korea; Department of Biomedical Science, Graduate School of Medicine, Korea University, Seoul, South Korea.
Department of Internal Medicine, Anam Hospital Korea University Medical Center, Seoul, South Korea.
Biochem Pharmacol. 2021 Aug;190:114658. doi: 10.1016/j.bcp.2021.114658. Epub 2021 Jun 17.
Chronic myeloid leukemia (CML) is a reciprocal translocation disorder driven by a breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) fusion gene that stimulates abnormal tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) are effective in treating Philadelphia chromosome (Ph) + CML patients. However, the appearance of TKI-resistant CML cells is a hurdle in CML treatment. Therefore, it is necessary to identify novel alternative treatments targeting tyrosine kinases. This study was designed to determine whether C-X-C chemokine receptor 2 (CXCR2) could be a novel target for TKI-resistant CML treatment. Interleukin 8 (IL-8), a CXCR2 ligand, was significantly increased in the bone marrow serum of initially diagnosed CML patients and TKI-resistant CML cell conditioned media. CXCR2 antagonists suppressed the proliferation of CML cells via cell cycle arrest in the G2/M phase. CXCR2 inhibition also attenuated mTOR, c-Myc, and BCR-ABL expression, leading to CML cell apoptosis, irrespective of TKI responsiveness. Moreover, SB225002, a CXCR2 antagonist, caused higher cell death in TKI-resistant CML cells than TKIs. Using a mouse xenograft model, we confirmed that SB225002 suppresses tumor growth, with a prominent effect on TKI-resistant CML cells. Our findings demonstrate that IL-8 is a prognostic factor for the progression of CML. Inhibiting the CXCR2-mTOR-c-Myc cascade is a promising therapeutic strategy to overcome TKI-sensitive and TKI-insensitive CML. Thus, CXCR2 blockade is a novel therapeutic strategy to treat CML, and SB225002, a commercially available CXCR2 antagonist, might be a candidate drug that could be used to treat TKI-resistant CML.
慢性髓性白血病（CML）是一种由断点簇集区（BCR）-阿贝尔逊白血病病毒（ABL）融合基因驱动的相互易位疾病，该融合基因会刺激异常的酪氨酸激酶活性。酪氨酸激酶抑制剂（TKIs）对治疗费城染色体（Ph）阳性的CML患者有效。然而，TKI耐药的CML细胞的出现是CML治疗中的一个障碍。因此，有必要确定针对酪氨酸激酶的新型替代疗法。本研究旨在确定C-X-C趋化因子受体2（CXCR2）是否可能成为TKI耐药CML治疗的新靶点。白细胞介素8（IL-8）作为CXCR2的配体，在初诊CML患者的骨髓血清和TKI耐药CML细胞条件培养基中显著升高。CXCR2拮抗剂通过使细胞周期停滞在G2/M期来抑制CML细胞的增殖。无论TKI反应性如何，CXCR2抑制还会减弱mTOR、c-Myc和BCR-ABL的表达，导致CML细胞凋亡。此外，CXCR2拮抗剂SB225002在TKI耐药的CML细胞中比TKIs引起更高的细胞死亡。使用小鼠异种移植模型，我们证实SB225002可抑制肿瘤生长，对TKI耐药的CML细胞有显著作用。我们的研究结果表明，IL-8是CML进展的一个预后因素。抑制CXCR2-mTOR-c-Myc级联反应是克服TKI敏感和TKI不敏感CML的一种有前景的治疗策略。因此，CXCR2阻断是治疗CML的一种新型治疗策略，市售的CXCR2拮抗剂SB225002可能是一种可用于治疗TKI耐药CML的候选药物。
