Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the occurrence of the t(9;22)(q34;q11) translocation. First-line therapy for CML consists of treatment with imatinib mesylate, which selectively inhibits the BCR-ABL protein by competing for its ATP-binding site. Adenine nucleotide signaling is modulated by the ectonucleotidases and this pathway is related to tumorigenic processes. Considering the relationship between ATP and cancer, we aimed to evaluate the influence of imatinib mesylate on the expressions and functions of the NTPDase and ecto-5′-nucleotidase (CD73) enzymes in imatinib-sensitive and -resistant K-562 cell lines. mRNA analysis showed that K-562 cells express all ENTPDs and NT5E. However, when treated with imatinib mesylate for 24 h, the expression of ENTPD1, -2, -3 and -5 increased, leading to a higher nucleotides hydrolysis rate. HPLC analysis identified increased ATP degradation in cells after 24 h of treatment, with consequent ADP and AMP formation, corroborating the increase in gene and protein expression of ectonucleotidases as observed in previous results. On the other hand, we observed that imatinib-resistant K-562 cells presented a decrease in nucleotide hydrolysis and expressions of ENTPD1 and -5. These results suggest an involvement of imatinib in modulating ectonucleotidases in CML that will need further investigation. Since these ectonucleotidases have important catalytic activities in the tumor microenvironment, their modulation in CML cells may represent an important therapeutic approach to regulate levels of extracellular adenine nucleotides.

中文翻译：

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甲磺酸伊马替尼影响慢性粒细胞白血病细胞系中细胞外 ATP 分解代谢和 NTPDase 表达。


慢性粒细胞白血病 (CML) 是一种骨髓增生性肿瘤，其特征是发生 t(9;22)(q34;q11) 易位。 CML 的一线治疗包括甲磺酸伊马替尼治疗，它通过竞争 ATP 结合位点选择性抑制 BCR-ABL 蛋白。腺嘌呤核苷酸信号传导受核酸外切酶调节，该途径与致瘤过程相关。考虑到ATP与癌症之间的关系，我们旨在评估甲磺酸伊马替尼对伊马替尼敏感和耐药的K-562细胞系中NTPDase和5′-核酸外切酶（CD73）表达和功能的影响。 mRNA分析显示K-562细胞表达所有ENTPDs和NT5E 。然而，当用甲磺酸伊马替尼处理24小时时， ENTPD1 、 -2、-3和-5的表达增加，导致核苷酸水解率更高。 HPLC 分析发现处理 24 小时后细胞中 ATP 降解增加，随后形成 ADP 和 AMP，证实了之前结果中观察到的外切核苷酸酶基因和蛋白质表达的增加。另一方面，我们观察到伊马替尼耐药的 K-562 细胞呈现核苷酸水解和ENTPD1和-5表达的减少。这些结果表明伊马替尼参与调节 CML 中的核酸酶，这需要进一步研究。由于这些核酸外切酶在肿瘤微环境中具有重要的催化活性，因此它们在 CML 细胞中的调节可能代表调节细胞外腺嘌呤核苷酸水平的重要治疗方法。