A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome
A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome
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DOI：
10.1124/mol.105.021311
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发表时间：
2006-07-01
影响因子：
3.6
通讯作者：
Huang, Peng
中科院分区：
文献类型：
--
作者：
Achanta, Geetha;Modzelewska, Aneta;Huang, Peng
查尔酮及其衍生物已被证明具有有效的抗癌活性。然而，细胞毒活性的确切机制仍有待确定。在这项研究中，我们评估了一系列硼查尔酮的抗癌活性和作用机制。在测试的八种查尔酮衍生物中，3,5-双-(4-硼酸-亚苄基)-1-甲基-哌啶-4-酮 (AM114) 在 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物测定和集落形成中表现出最强的生长抑制活性，IC50 值为 1.5 和 0.6 μM 分别进行测定。 AM114 的细胞毒活性与 p53 和 p21 蛋白的积累以及细胞凋亡的诱导有关。机制研究表明，AM114 处理可抑制体外 20S 蛋白酶体的胰凝乳蛋白酶样活性，导致全细胞中泛素化 p53 和其他细胞蛋白的显着积累。体外研究表明，AM114 不会显着破坏 p53 和鼠双分钟 2 蛋白的相互作用。值得注意的是，AM114 作为单一药物优先对野生型 p53 表达的细胞产生毒性，而该化合物与电离辐射 (IR) 的组合显着增强了 IR 在野生型 p53 和 p53 缺失细胞中的细胞杀伤活性。总之，这些结果表明硼查尔酮衍生物 AM114 通过抑制细胞蛋白酶体在癌细胞中诱导显着的细胞毒作用，并为进一步开发此类化合物作为新型癌症化疗剂提供了理论基础。
Chalcones and their derivatives have been shown to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1- methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 mu M in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It is noteworthy that AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell-killing activity of IR in both wild-type p53 and p53-null cells. Together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.