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首页> 外文期刊>Cell cycle >EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1.
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EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1.

机译：EF24是一种新型姜黄素类似物，可破坏微管细胞骨架并抑制HIF-1。

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Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.
机译：姜黄素是香料姜黄的黄色颜料，由于其抗增殖和抗血管生成特性，已成为一种有前途的抗癌剂。但是，该化合物的分子作用机理仍是争论的话题。另外，姜黄素在体内的低生物利用度和功效特征进一步阻碍了其临床发展。这项研究的重点是EF24的作用机理，EF24是一种新型姜黄素类似物，具有比姜黄素更高的生物活性和生物利用度，但没有增加的毒性。用EF24或姜黄素治疗MDA-MB231乳腺癌和PC3前列腺癌细胞导致抑制HIF-1alpha蛋白水平，并因此抑制HIF转录活性。这种药物诱导的HIF抑制以VHL依赖性但不依赖蛋白酶体的方式发生。我们发现，虽然姜黄素抑制HIF-1alpha基因转录，但EF24通过转录后抑制HIF-1alpha发挥其活性。该结果表明这两种化合物在结构上相似但在机理上不同。进一步区分这两种化合物的另一种细胞效应是EF24而非姜黄素诱导细胞中微管稳定的能力。在使用纯化的牛脑微管蛋白的体外测定中，EF24对微管蛋白的聚合没有稳定作用，这表明EF24诱导的细胞内细胞骨架破坏可能是上游信号事件的结果，而不是EF24直接结合微管蛋白。总而言之，我们的研究将EF24鉴定为具有独特作用机制的新型姜黄素相关化合物，我们认为这有助于该药的有效抗癌活性，并可进一步用于研究EF24的治疗潜力。

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