Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia.
Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia.
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DOI：
10.1371/journal.pone.0100960
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Zhang H;Gu L;Liu T;Chiang KY;Zhou M
尼洛替尼是一种与伊马替尼相关的选择性BCR-ABL酪氨酸激酶抑制剂，比伊马替尼更有效。尼洛替尼被广泛用于治疗慢性粒细胞白血病（CML）和费城阳性（Ph+）急性淋巴细胞白血病（ALL）。本研究将小鼠双微体2同源物（MDM 2）确定为尼洛替尼的靶点。在研究ALL细胞系时，我们发现尼洛替尼以剂量和时间依赖性方式显著抑制费城阳性（Ph+）和费城阴性（Ph-）ALL细胞中MDM 2的表达。进一步研究表明，尼洛替尼通过诱导MDM 2自身泛素化和降解，在翻译后水平抑制MDM 2。尼洛替尼介导的MDM 2下调未导致p53蓄积和激活。尼洛替尼处理的ALL细胞中MDM 2的抑制导致抗凋亡蛋白X连锁凋亡抑制蛋白（XIAP）（MDM 2的翻译靶点）下调，从而激活半胱天冬酶。尼洛替尼介导的MDM 2下调后抑制XIAP导致表达MDM 2的ALL细胞凋亡;然而，相似的尼洛替尼治疗诱导Ph+/MDM 2 + ALL细胞凋亡的强度高于Ph-/MDM 2+或Ph+/MDM 2- ALL。Ph-/MDM 2-的ALL细胞对尼洛替尼完全耐药。这些结果表明，尼洛替尼可抑制MDM 2并通过下调XIAP诱导p53非依赖性凋亡途径;因此，尼洛替尼不仅可治疗Ph+，还可治疗癌细胞过度表达MDM 2的Ph- ALL患者。
Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor related to imatinib that is more potent than imatinib. Nilotinib is widely used to treat chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The present study identifies Mouse double minute 2 homolog (MDM2) as a target of nilotinib. In studying ALL cell lines, we found that the expression of MDM2 in both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) ALL cells was remarkably inhibited by nilotinib, in a dose- and time-dependent manner. Further studies demonstrated that nilotinib inhibited MDM2 at the post-translational level by inducing MDM2 self-ubiquitination and degradation. Nilotinib-mediated MDM2 downregulation did not result in accumulation and activation of p53. Inhibition of MDM2 in nilotinib-treated ALL cells led to downregulation of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP), a translational target of MDM2, resulting in activation of caspases. Inhibition of XIAP following nilotinib-mediated downregulation of MDM2 resulted in apoptosis of MDM2-expressing ALL; however, similar nilotinib treatment induced stronger apoptosis in Ph+/MDM2+ ALL than in Ph-/MDM2+ or Ph+/MDM2- ALL. The ALL cells that were Ph-/MDM2- were totally resistant to nilotinib. These results suggested that nilotinib can inhibit MDM2 and induce a p53-independent apoptosis pathway by downregulating XIAP; thus, nilotinib can treat not only Ph+, but also Ph- ALL patients whose cancer cells overexpress MDM2.
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影响因子：
50.3
作者：
Gu L;Zhu N;Zhang H;Durden DL;Feng Y;Zhou M
通讯作者：
Zhou M
影响因子：
1.7
作者：
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Gustafsson, B
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20.3
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158.5
作者：
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影响因子：
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Huang M;Zhang H;Liu T;Tian D;Gu L;Zhou M
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Zhou M