1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase
1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase
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1,4-二氨基-2,3-二氰基-1,4-双(甲硫基)丁二烯 (U0126) 增强 Combretastatin A4 的细胞毒性，不依赖于丝裂原激活的蛋白激酶激酶
DOI：
10.1124/jpet.109.153320
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Lou, Liguang
中科院分区：
文献类型：
--
作者：
Quan, Haitian;Liu, Houfu;Lou, Liguang
康布他汀 A4 (CA4) 是一种新型血管干扰剂，通过抑制微管组装和随后破坏肿瘤血流，显示出良好的抗癌作用。在本报告中，我们证明 1,4-二氨基-2,3-二氰基-1,4-双（甲硫基）丁二烯 (U0126) 是一种丝裂原激活蛋白激酶激酶 (MEK) 的选择性抑制剂，可显着增强 BEL-7402 细胞中 CA4 的细胞毒性，而与 MEK 抑制无关。另一种更特异的 MEK 抑制剂 PD0325901 [N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-[2-氟-4-碘-苯氨基]-苯甲酰胺]不具有与 U0126 相同的效果，这一事实证明了这种独立性。由于 CA4 的葡萄糖醛酸化失活，分解的微管能够在 CA4 处理的后期重新组装。 U0126（而非 PD0325901）抑制 CA4 葡萄糖醛酸化，从而阻断微管重新组装并增强 CA4 诱导的 G2/M 细胞周期停滞。与此一致的是，U0126显着增强CA4诱导的对发生CA4葡萄糖醛酸化的细胞的细胞毒性，但对不发生这种葡萄糖醛酸化的细胞则不显着增强。这些结果表明，在解释使用 U0126 获得的数据或在临床实践中将 CA4 与葡萄糖醛酸化抑制剂联合使用时应格外小心。最重要的是要注意，这些发现表明 CA4 与葡萄糖醛酸化抑制剂的组合可能是一种新颖且合理的癌症治疗策略。
Combretastatin A4 (CA4) is a novel vascular-disrupting agent that has shown promising anticancer effects through its inhibition of microtubule assembly and subsequent disruption of tumor blood flow. In this report, we demonstrate that 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126), a selective inhibitor of mitogen-activated protein kinase kinase (MEK), significantly enhances the cytotoxicity of CA4 in BEL-7402 cells, independently of MEK inhibition. This independence is evidenced by the fact that another, more specific MEK inhibitor, PD0325901 [N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-[2-fluoro-4-iodo-phenylamino]-benzamide], does not have the same effect as U0126. The disassembled microtubules are able to reassemble in the later stages of CA4 treatment, because of the inactivating glucuronidation of CA4. U0126, but not PD0325901, inhibits CA4 glucuronidation, thereby blocking microtubule reassembly and enhancing CA4-induced G2/M cell-cycle arrest. Consistent with this, U0126 significantly enhances CA4-induced cytotoxicity for cells in which CA4 glucuronidation occurs, but not for cells in which such glucuronidation does not occur. These results suggest that great caution should be exercised when interpreting data obtained using U0126 or when CA4 is combined with inhibitors of glucuronidation in clinical practice. It is most important to note that these findings indicate that the combination of CA4 with inhibitors of glucuronidation may be a novel and rational strategy for cancer therapy.