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首页> 美国卫生研究院文献>International Journal of Biological Sciences >In Vitro Antileukemia Activity of ZSTK474 on K562 and Multidrug Resistant K562/A02 Cells
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In Vitro Antileukemia Activity of ZSTK474 on K562 and Multidrug Resistant K562/A02 Cells

机译：ZSTK474对K562和耐多药K562 / A02细胞的体外抗白血病活性

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Chronic myelogenous leukemia (CML) is a malignant hematological disorder mainly caused by the Bcr-Abl tyrosine kinase. While Bcr-Abl inhibitors including Imatinib showed antitumor efficacy on many CML patients, resistance was frequently reported in recent years. Therefore, novel drugs for CML are still expected. ZSTK474 is a specific phosphatidylinositol 3-kinase (PI3K) inhibitor that we identified. In the present study, the efficacy of ZSTK474, alone or in combination with Imatinib, on K562 CML cells as well as on its multidrug resistance counterpart K562/A02 cells, was investigated. ZSTK474 inhibited the cell proliferation with an IC50 of 4.69 μM for K562 and 7.57 μM for K562/A02 cells, respectively. Treatment by ZSTK474 resulted in cell cycle arrest in G1 phase, which might be associated with upregulation of p27, and downregulation of cyclin D1. ZSTK474 also inhibited phosphorylation of Akt and GSK-3β, which might be involved in the effect on the above cell cycle-related proteins. Moreover, combination of ZSTK474 and Imatinib indicated synergistic effect on both cell lines. In conclusion, ZSTK474 exhibited antileukemia activity alone, and showed synergistic effect when combined with Imatinib, on CML K562 cells as well as the multidrug resistant ones, providing a potential therapeutic approach for CML patients.
机译：慢性粒细胞性白血病（CML）是一种恶性血液病，主要由Bcr-Abl酪氨酸激酶引起。尽管包括伊马替尼在内的Bcr-Abl抑制剂对许多CML患者显示出抗肿瘤功效，但近年来经常报道耐药性。因此，仍然期望用于CML的新药。 ZSTK474是我们鉴定出的一种特异性磷脂酰肌醇3-激酶（PI3K）抑制剂。在本研究中，研究了ZSTK474单独或与伊马替尼组合对K562 CML细胞及其对多药耐药的K562 / A02细胞的功效。 ZSTK474抑制细胞增殖，K562的IC50为4.69μM，K562 / A02细胞的IC50为7.57μM。 ZSTK474处理导致细胞周期停滞在G1期，这可能与p27的上调和细胞周期蛋白D1的下调有关。 ZSTK474还抑制Akt和GSK-3β的磷酸化，这可能与上述细胞周期相关蛋白的作用有关。此外，ZSTK474和伊马替尼的组合表明对两种细胞系均具有协同作用。总之，ZSTK474仅表现出抗白血病作用，并且与伊马替尼联合使用时，对CML K562细胞和多药耐药细胞具有协同作用，为CML患者提供了潜在的治疗方法。

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