Dual antitumor mechanisms of Notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model
Dual antitumor mechanisms of Notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model
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DOI：
10.1111/j.1349-7006.2009.01328.x
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发表时间：
2009-12-01
期刊：
影响因子：
5.7
通讯作者：
Chiba, Shigeru
中科院分区：
文献类型：
--
作者：
Masuda, Shigeo;Kumano, Keiki;Chiba, Shigeru
Notch信号传导的组成性激活是人类T细胞急性淋巴细胞白血病（T-ALL）亚组增殖所必需的。先前的体外研究已经证明了Notch信号传导抑制剂治疗T-ALL的治疗潜力。为了进一步研究这种可能性，我们将γ-分泌酶抑制剂（GSI）应用于T-ALL异种移植模型。用GSI治疗已建立的皮下肿瘤导致来自四种T-ALL细胞系的肿瘤部分或完全消退，这些细胞系在体外也对GSI敏感。为了阐明作用机制，我们用Notch 1（aN 1）的活性形式转导DND-41细胞，其赋予对体外GSI处理的抗性。然而，在体内用GSI治疗诱导从aN 1转导的DND-41细胞发展的皮下肿瘤的部分但显著的消退，而它诱导从模拟转导的DND-41细胞发展的肿瘤的完全消退。这些发现表明，GSI的显著疗效可能归因于双重机制，直接通过抑制细胞自主的Notch信号转导而使DND-41细胞凋亡，以及间接通过抑制非细胞自主的Notch信号转导而干扰肿瘤血管生成。（Cancer Sci 2009; 100：2444-2450）。
Constitutive activation of Notch signaling is required for the proliferation of a subgroup of human T-cell acute lymphoblastic leukemias (T-ALL). Previous in vitro studies have demonstrated the therapeutic potential of Notch signaling inhibitors for treating T-ALL. To further examine this possibility, we applied a gamma-secretase inhibitor (GSI) to T-ALL xenograft models. Treatment of established subcutaneous tumors with GSI resulted in partial or complete regression of tumors arising from four T-ALL cell lines that were also sensitive to GSI in vitro. To elucidate the mechanism of action, we transduced DND-41 cells with the active form of Notch1 (aN1), which conferred resistance to in vitro GSI treatment. Nevertheless, in vivo treatment with GSI induced a partial but significant regression of subcutaneous tumors that developed from aN1-transduced DND-41 cells, whereas it induced complete regression of tumors that developed from mock-transduced DND-41 cells. These findings indicate that the remarkable efficacy of GSI might be attributable to dual mechanisms, directly via apoptosis of DND-41 cells through the inhibition of cell-autonomous Notch signaling, and indirectly via disturbance of tumor angiogenesis through the inhibition of non-cell-autonomous Notch signaling. (Cancer Sci 2009; 100: 2444-2450).