Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells.
Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells.
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发表时间：
2011-03
影响因子：
2
通讯作者：
Yuki Okuhashi;M. Itoh;N. Nara;S. Tohda
中科院分区：
文献类型：
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作者：
Yuki Okuhashi;M. Itoh;N. Nara;S. Tohda
背景：γ-分泌酶抑制剂(GSI)是一种很有前途的抗白血病分子靶向治疗药物。然而，它们只显示出有限的有效性。我们认为GSI与Hedgehog抑制剂和Wnt抑制剂联合使用可能会提高疗效，因为这些信号通路对白血病细胞的生长也很重要。材料与方法检测GSI-XXI联合Hedgehog抑制剂环丙胺(Cy)和Wnt抑制剂槲皮素(Qu)对3株NOTCH1突变的T细胞急性淋巴细胞白血病(T-ALL)细胞株和3株急性髓系白血病细胞株的体外生长、集落形成和Notch1蛋白表达的影响。结果GSI中加入Cy或Qu后，对DND-41T-ALL细胞的生长抑制作用分别为相加或协同作用。有趣的是，Cy和Qu处理降低了DND-41细胞中Notch1蛋白及其活性片段，这表明Notch信号与Hedgehog或Wnt信号有关。GSI中加入Cy或Qu后，Notch1的活性和表达均下降。结论GSI与Cy或Qu联用可增强GSI的抗白血病作用，通过体外药敏试验选择合适的病例。
BACKGROUND The Notch inhibitors, γ-secretase inhibitors (GSIs), are promising candidates for molecular targeted therapy against leukemia. However, they show only limited effectiveness. We thought that the efficacy of GSIs might be improved by their combination with Hedgehog inhibitors and Wnt inhibitors because these signaling pathways are also important for the growth of leukemia cells. MATERIALS AND METHODS The effects of the combination of GSI-XXI plus the Hedgehog inhibitor, cyclopamine (Cy), or the Wnt inhibitor, quercetin (Qu), on the in vitro cell growth, colony formation and Notch1 protein expression of three T-cell acute lymphoblastic leukemia (T-ALL) cell lines with NOTCH1 mutations and three acute myeloid leukemia cell lines were examined. RESULTS The addition of Cy or Qu to GSI suppressed the growth of DND-41 T-ALL cells additively or synergistically, respectively. Interestingly, Cy treatment and Qu treatment reduced Notch1 protein and its active fragment in DND-41 cells, which suggests a relationship between Notch signaling and Hedgehog or Wnt signaling. The addition of Cy or Qu to GSI promoted the decrease of Notch1 activation and expression. CONCLUSION The anti-leukemic effects of a GSI could be promoted by its combination with Cy or Qu, in appropriate cases selected by in vitro drug sensitivity test.