Ertmer A, Huber V, Gilch S, Yoshimori T, Erfle V, Duyster J, Elsässer H-P, Schätzl H M
Institute of Virology, Technical University of Munich, Munich, Germany.
Leukemia. 2007 May;21(5):936-42. doi: 10.1038/sj.leu.2404606. Epub 2007 Mar 1.
The tyrosine kinase inhibitor imatinib (Gleevec, Novartis Pharmaceuticals Corporation; Basel, Switzerland) is a powerful drug for treatment of chronic myelogenous leukemia (CML) and other malignancies. It selectively targets various tyrosine kinases, thereby leading to growth arrest of respective cancer cells. Given its wide application, it is of high importance to know all related underlying molecular mechanisms. We had previously found that imatinib increases the cellular clearance of intracellular protein aggregates by targeting the abl pathway and thereby upregulating lysosomal activity. Here, we describe that imatinib dose dependently activates the cellular autophagy machinery in mammalian cells, independently of tissue type, species origin or immortalization status of cells. Autophagy is an archetypical cellular degradation mechanism implicated in many physiological and pathophysiological conditions. Our data link for the first time the process of autophagy with the mode of action of imatinib. Induction of autophagy might represent an additional mechanism of imatinib to induce growth arrest, promote apoptosis in cancer cells and eventually even promote tumour regression.
酪氨酸激酶抑制剂伊马替尼（格列卫，诺华制药公司；瑞士巴塞尔）是治疗慢性粒细胞白血病（CML）和其他恶性肿瘤的强效药物。它选择性地作用于多种酪氨酸激酶，从而导致相应癌细胞的生长停滞。鉴于其广泛应用，了解所有相关的潜在分子机制至关重要。我们之前发现，伊马替尼通过靶向abl途径并上调溶酶体活性，增加细胞内蛋白质聚集体的细胞清除率。在此，我们描述伊马替尼在哺乳动物细胞中剂量依赖性地激活细胞自噬机制，这与细胞的组织类型、物种来源或永生化状态无关。自噬是一种典型的细胞降解机制，涉及许多生理和病理生理状况。我们的数据首次将自噬过程与伊马替尼的作用方式联系起来。自噬的诱导可能代表伊马替尼诱导生长停滞、促进癌细胞凋亡并最终促进肿瘤消退的另一种机制。
