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首页> 外文期刊>Cell cycle >Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells
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Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells

机译：PI3K和SRC激酶抑制剂与伊马替尼对CML-PBL细胞内细胞内钙水平，自噬和凋亡的联合作用

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摘要

Imatinib induces a complete cytogenetic regression in a large percentage of patients affected by chronic myeloid leukemia (CML) until mutations in the kinase domain of BCR-ABL appear. Alternative strategies for CML patients include the inhibition of phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR ) pathway, which is constitutively activated in leukemia cells and seems important for the regulation of cell proliferation, viability, and autophagy. In this study, we verified the effect of imatinib mesylate (IM), alone or in association with LY294002 (LY) (a specific PI3K protein tyrosine kinase inhibitor) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) (a Src tyrosine kinase inhibitor), on viability, intracellular calcium mobilization, apoptosis, and autophagy, in order to verify possible mechanisms of interaction. Our data demonstrated that PP1 and LY interact synergistically with IM by inducing apoptosis and autophagy in Bcr/Abl+ leukemia cells and this mechanism is related to the stress of the endoplasmic reticulum (ER ). Our findings suggest a reasonable relationship between apoptotic and autophagic activity of tyrosine kinase inhibitors (TKIs) and the functionality of smooth ER Ca2+-AT Pase and inositol triphosphate receptors, independently of intracellular calcium levels. Therapeutic strategies combining imatinib with PI3K and/or Src kinase inhibitors warrant further investigations in Bcr/Abl+ malignancies, particularly in the cases of imatinib mesylate-resistant disease.
机译：伊马替尼在大部分受慢性髓样白血病（CML）影响的患者中诱导完全的细胞遗传学衰退，直到BCR-ABL激酶结构域出现突变。 CML患者的替代策略包括抑制雷帕霉素（mTOR）途径的磷脂酰肌醇3激酶（PI3K）-Akt-哺乳动物靶标，该靶标在白血病细胞中被组成性激活，对于调节细胞增殖，生存力和自噬似乎很重要。在这项研究中，我们验证了甲磺酸伊马替尼（IM）单独或与LY294002（LY）（一种特定的PI3K蛋白酪氨酸激酶抑制剂）或4-氨基-5-（4-甲基苯基）-7-（t -丁基）吡唑并[3,4-d]-嘧啶（PP1）（一种Src酪氨酸激酶抑制剂），涉及生存能力，细胞内钙动员，细胞凋亡和自噬，以验证可能的相互作用机制。我们的数据表明，PP1和LY通过诱导Bcr / Abl +白血病细胞凋亡和自噬而与IM协同相互作用，并且这种机制与内质网（ER）的应激有关。我们的发现表明酪氨酸激酶抑制剂（TKIs）的凋亡和自噬活性与光滑的ER Ca2 + -AT Pase和肌醇三磷酸受体的功能之间存在合理的关系，而与细胞内钙水平无关。将伊马替尼与PI3K和/或Src激酶抑制剂联合使用的治疗策略值得进一步研究Bcr / Abl +恶性肿瘤，尤其是对甲磺酸伊马替尼耐药的疾病。

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