Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma
Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma
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DOI：
10.1158/1535-7163.mct-08-0669
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发表时间：
2009-02-01
影响因子：
5.7
通讯作者：
de Groot, John
中科院分区：
文献类型：
--
作者：
Milano, Vanessa;Piao, Yuji;de Groot, John
胶质母细胞瘤的定义是侵袭性侵袭、微血管增生和中央坏死。BMS-354825（达沙替尼）是一种ATP竞争性小分子抑制剂，通过阻断在肿瘤发生中至关重要的酪氨酸磷酸化位点，可有效治疗具有突变型BCR-ABL、KIT和表皮生长因子受体的耐药肿瘤。在研究达沙替尼在人胶质母细胞瘤中的作用时，我们发现在基线和表皮生长因子刺激后，用低纳摩尔浓度的达沙替尼处理的细胞系中磷酸化SRC、AKT和核糖体蛋白S6的水平降低。此外，在具有功能性PTEN的胶质瘤细胞中注意到对达沙替尼的敏感性增加。在远低于达沙替尼IC 50的浓度下，在体外观察到侵袭潜力降低，免疫荧光染色证实了这一点，显示桩蛋白定位于粘着斑的破坏和粘着斑激酶自磷酸化的降低。细胞周期分析显示，用吖啶橙子染色评估达沙替尼处理的胶质瘤细胞中，G（1）阻滞最小，但自噬细胞死亡显著增加，轻链3表达和加工也随之增加。用达沙替尼和替莫唑胺联合治疗胶质瘤细胞导致细胞周期破坏和自噬细胞死亡显著增加。与达沙替尼联合卡铂或伊立替康相比，达沙替尼联合替莫唑胺更有效地提高了替莫唑胺的疗效。这些结果强烈支持达沙替尼在胶质母细胞瘤治疗中的临床应用，并为达沙替尼和替莫唑胺联合治疗提供了依据。[Mol癌症治疗2009;8（2）：394-406]
Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC50 of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G(1) arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide. [Mol Cancer Ther 2009;8(2):394-406]