Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea.
Disease Target Structure Research Center, KRIBB, Daejeon, 34141, South Korea; Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, South Korea.
Biochem Biophys Res Commun. 2019 Jun 25;514(2):518-523. doi: 10.1016/j.bbrc.2019.04.009. Epub 2019 May 2.
Irinotecan is a strong anticancer drug whose mechanism of action has been reported only for the inhibition of DNA topoisomerase I (Topo I) through its active metabolite SN-38. In this study, we present a new mechanism of Irinotecan which inhibits the activities of MDM2, an E3 ligase of tumour suppressor p53, and Bcl-xL, an anti-apoptotic protein, through direct binding. In our structure modelling study, Irinotecan could fit to the binding sites of MDM2 and Bcl-xL for their known drugs, Nutlin-3 and ABT-737, with a better binding affinity than to Topo I. The direct binding of Irinotecan to both proteins was confirmed through a NMR study. We further showed that Irinotecan increased the amount of p53 only in the presence of MDM2 and inhibited the physical interaction of Bcl-xL with Bim, a core pro-apoptotic protein. In addition, we demonstrated that Irinotecan induced the down regulation of proliferation and strong G2/M arrest in HCT116 colon cancer cells shortly after treatment. Collectively, we suggest a new mechanism of action for Irinotecan as a dual target inhibitor of MDM2 and Bcl-xL facilitating the anticancer activities mediated by p53 and Bcl-xL interaction partners.
伊立替康是一种强效抗癌药物，其作用机制仅通过其活性代谢物 SN-38 抑制 DNA 拓扑异构酶 I（Topo I）得到报道。在本研究中，我们提出了伊立替康的一种新机制，即通过直接结合抑制肿瘤抑制因子 p53 的 E3 连接酶 MDM2 和抗凋亡蛋白 Bcl-xL 的活性。在我们的结构建模研究中，伊立替康可以与 MDM2 和 Bcl-xL 的结合位点结合，其与已知药物 Nutlin-3 和 ABT-737 的结合亲和力优于 Topo I。通过 NMR 研究证实了伊立替康与这两种蛋白的直接结合。我们进一步表明，伊立替康仅在存在 MDM2 的情况下增加 p53 的含量，并抑制 Bcl-xL 与 Bim（一种核心促凋亡蛋白）的物理相互作用。此外，我们证明伊立替康在治疗后不久即可诱导 HCT116 结肠癌细胞的增殖减少和强烈的 G2/M 期阻滞。总之，我们提出了伊立替康作为 MDM2 和 Bcl-xL 的双重靶标抑制剂的作用机制，促进了 p53 和 Bcl-xL 相互作用伙伴介导的抗癌活性。
