Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
Eur J Pharmacol. 2017 Jun 5;804:52-56. doi: 10.1016/j.ejphar.2017.03.040. Epub 2017 Mar 18.
Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cytotoxicity in c-KIT-positive cells than c-KIT-negative cells from AML patients. To address this issue, cell lines with high c-KIT expression, HEL92.1.7, and moderate c-KIT expression, H209, were selected. HEL92.1.7 cells were grouped into intermediate and high c-KIT expression populations. The cytotoxicity of radotinib against the HEL92.1.7 cell population with intermediate c-KIT expression was not different from that of the population with high c-KIT expression. When H209 cells were grouped into c-KIT expression-negative and c-KIT expression-positive populations, radotinib induced cytotoxicity in the c-KIT-positive population, but not the c-KIT-negative population. Thus, radotinib induces cytotoxicity in c-KIT-positive cells, regardless of the c-KIT expression intensity. Therefore, radotinib induces significant cytotoxicity in c-KIT-positive AML cells, suggesting that radotinib is a potential target agent for the treatment of c-KIT-positive malignancies including AML.
先前，我们报道了 BCR-ABL1 酪氨酸激酶抑制剂罗替尼（radotinib）可诱导急性髓系白血病（AML）细胞的细胞毒性。然而，罗替尼在 c-KIT 阳性 AML 细胞亚群中的作用尚不清楚。我们观察到低浓度罗替尼对来自 AML 患者的 c-KIT 阳性细胞比 c-KIT 阴性细胞具有更强的细胞毒性。为了解决这个问题，选择了高 c-KIT 表达的细胞系 HEL92.1.7 和中等 c-KIT 表达的细胞系 H209。将 HEL92.1.7 细胞分为中高 c-KIT 表达群体。具有中等 c-KIT 表达的 HEL92.1.7 细胞群体对罗替尼的细胞毒性与高 c-KIT 表达的群体没有差异。当将 H209 细胞分为 c-KIT 阴性和 c-KIT 阳性群体时，罗替尼诱导 c-KIT 阳性群体的细胞毒性，但不诱导 c-KIT 阴性群体的细胞毒性。因此，罗替尼诱导 c-KIT 阳性细胞的细胞毒性，而与 c-KIT 表达强度无关。因此，罗替尼可诱导 c-KIT 阳性 AML 细胞产生显著的细胞毒性，这表明罗替尼是治疗包括 AML 在内的 c-KIT 阳性恶性肿瘤的潜在靶向药物。
