Zhong Jiansheng, Zhang Jinli, Yu Xiaoyang, Zhang Xing, Dian Linping
Department of Hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China (mainland).
Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China (mainland).
Med Sci Monit. 2020 Aug 24;26:e924922. doi: 10.12659/MSM.924922.
BACKGROUND Drug resistance is a major problem in the treatment of leukemia with doxorubicin (Dox), and the erythroblastosis virus E26 oncogene homolog 1 (ETS1) gene is associated with drug resistance. Olmutinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) reported to play a role in reversing multidrug resistance (MDR) in cancer cells. The objective of this study was to investigate whether olmutinib could reverse Dox resistance in leukemia cells overexpressing ETS1. MATERIAL AND METHODS Human chronic myelogenous leukemia cell line K562 and its Dox-resistant cell line K562/ADR were used. Western blot and qPCR detected the expression of ETS1 and ABCB1. Cell proliferation was measured by cell counting kit-8 and methyl thiazolyl tetrazolium. Cell apoptosis was observed by western blot and flow cytometry. A nude mice K562/ADR xenograft model was used to investigate the inhibitory effects of olmutinib on tumor growth in vivo. RESULTS The mRNA and protein expressions of ETS1 and ABCB1 were up-regulated in Dox-resistant leukemia cell line K562/ADR. We overexpressed ETS1 in both cell lines, finding that olmutinib inhibited the cell viability of K562 and K562/ADR in a concentration-dependent manner. The cytotoxicity of Dox to EST1-overexpressing K562/ADR cells was enhanced by olmutinib. Olmutinib also promoted apoptosis of K562 and K562/ADR cells compared with Dox treatment alone. In vivo, olmutinib enhanced the inhibitory effects of Dox on ETS1-overexpressing K562/ADR cell xenograft growth. CONCLUSIONS Our results suggest that the novel EGFR TKI olmutinib enhances the sensitivity of ETS1-overexpressing leukemia cells to Dox.
耐药性是阿霉素（Dox）治疗白血病的主要问题，而原癌基因ETS1与耐药性相关。奥莫替尼是一种第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），据报道其在逆转癌细胞多药耐药（MDR）中发挥作用。本研究的目的是探讨奥莫替尼是否能逆转过表达ETS1的白血病细胞对Dox的耐药性。
使用人慢性髓性白血病细胞系K562及其耐Dox细胞系K562/ADR。通过蛋白质免疫印迹法（Western blot）和定量聚合酶链反应（qPCR）检测ETS1和ABCB1的表达。采用细胞计数试剂盒-8（CCK-8）和甲基噻唑基四氮唑（MTT）法检测细胞增殖。通过蛋白质免疫印迹法和流式细胞术观察细胞凋亡。使用K562/ADR裸鼠异种移植模型研究奥莫替尼对体内肿瘤生长的抑制作用。
耐Dox白血病细胞系K562/ADR中ETS1和ABCB1的mRNA及蛋白表达上调。我们在两种细胞系中过表达ETS1，发现奥莫替尼以浓度依赖性方式抑制K562和K562/ADR的细胞活力。奥莫替尼增强了Dox对过表达EST1的K562/ADR细胞的细胞毒性。与单独使用Dox处理相比，奥莫替尼还促进了K562和K562/ADR细胞的凋亡。在体内，奥莫替尼增强了Dox对过表达ETS1的K562/ADR细胞异种移植生长的抑制作用。
我们的结果表明，新型EGFR TKI奥莫替尼可增强过表达ETS1的白血病细胞对Dox的敏感性。
