Spampinato Mariarita, Zuppelli Tatiana, Dulcamare Ilaria, Longhitano Lucia, Sambataro Domenico, Santisi Annalisa, Alanazi Amer M, Barbagallo Ignazio A, Vicario Nunzio, Parenti Rosalba, Romano Alessandra, Musumeci Giuseppe, Li Volti Giovanni, Palumbo Giuseppe A, Di Raimondo Francesco, Nicolosi Anna, Giallongo Sebastiano, Del Fabro Vittorio
Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, 95123 Catania, Italy.
Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.
Pharmaceuticals (Basel). 2024 Jul 5;17(7):894. doi: 10.3390/ph17070894.
Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML.
Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels.
Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models.
In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.
慢性髓系白血病是一种以白血病细胞异常增殖为特征的血液系统恶性肿瘤。尽管酪氨酸激酶抑制剂（如达沙替尼）取得了显著进展，但耐药性仍然是一个挑战。本研究的目的是探讨核输出蛋白1抑制剂塞利尼索提高酪氨酸激酶抑制剂对慢性髓系白血病有效性的潜力。
用人慢性髓系白血病细胞系（LAMA84和K562）分别用塞利尼索、达沙替尼或它们的组合进行处理。使用流式细胞术评估细胞凋亡、线粒体膜电位和线粒体质量。实时逆转录聚合酶链反应用于评估与线粒体功能相关基因的表达。蛋白质免疫印迹法和共聚焦显微镜检查了PINK和血红素加氧酶-1（HO-1）蛋白水平。
塞利尼索诱导慢性髓系白血病细胞系凋亡和线粒体去极化，降低细胞活力。达沙替尼/塞利尼索组合进一步增强了细胞毒性，改变了线粒体适应性，并下调了HO-1核转位，在不同模型中，HO-1核转位与耐药性有关。
总之，本研究表明达沙替尼/塞利尼索可能是一种有前景的慢性髓系白血病治疗策略，为新的靶向治疗提供了新的见解。
