Abstract

The dual phosphatases CDC25 are involved in cell cycle regulation and overexpressed in many tumours, including melanoma. CDC25 is a promising target for discovering anticancer drugs, and several studies focussed on characterisation of quinonoid CDC25 inhibitors, frequently causing undesired side toxic effects. Previous work described an optimisation of the inhibition properties by naphthylphenylamine (NPA) derivatives of NSC28620, a nonquinonoid CDC25 inhibitor. Now, the CDC25B•inhibitor interaction was investigated through fluorescence studies, shedding light on the different inhibition mechanism exerted by NPA derivatives. Among the molecular processes, mediating the specific and high cytotoxicity of one NPA derivative in melanoma cells, we observed decrease of phosphoAkt, increase of p53, reduction of CDC25 forms, cytochrome c cytosolic translocation and increase of caspase activity, that lead to the activation of an apoptotic programme. A basic knowledge on CDC25 inhibitors is relevant for discovering potent bioactive molecules, to be used as anticancer agents against the highly aggressive melanoma.

摘要

双重磷酸酶CDC25参与细胞周期调节，并在包括黑色素瘤在内的许多肿瘤中过表达。CDC25是发现抗癌药物的有希望的靶标，一些研究集中在醌类CDC25抑制剂的表征上，该抑制剂经常引起不良的副作用。先前的工作描述了NSC28620（一种非醌类CDC25抑制剂）的萘基苯胺（NPA）衍生物对抑制性能的优化。现在，通过荧光研究对CDC25B·抑制剂的相互作用进行了研究，揭示了NPA衍生物发挥的不同抑制机理。在分子过程中，介导一种NPA衍生物在黑素瘤细胞中的特异性和高细胞毒性，我们观察到磷酸化Akt降低，p53升高，CDC25形式减少，细胞色素减少c胞浆移位和caspase活性增加，导致凋亡程序的激活。CDC25抑制剂的基本知识与发现有效的生物活性分子有关，这些分子可用作抗高度侵袭性黑色素瘤的抗癌药。