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Activity of novel Cdc25 inhibitors and preliminary evaluation of their potentiation of chemotherapeutic drugs in human breast cancer cells

机译:新型Cdc25抑制剂的活性及其对人乳腺癌细胞化疗药物的增强作用的初步评估

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Dual-specific phosphatases Cdc25 play a critical role in the cell cycle regulation by activating kinases of Cdk/cyclin complexes. Three Cdc25 isoforms (A, B and C) have been identified in mammalians. Cdc25A and B display oncogenic properties and are over-expressed in different tumors. Cdc25 phosphatases are therefore attractive targets for therapeutic strategies. Novel maleic anhydride derivatives bearing a fatty acid chain of variable size have been synthesized and tested for their Cdc25 inhibitory potential using an in vitro assay. We report biological activity of ineffective, moderate, and efficient inhibitors on breast cancer cells (MCF7) and its counterpart resistant to vincristine (Vcr-R). The most potent compounds induced Cdk2 inhibition and accumulation in G0/G1 phase of the cell cycle. Moreover, apoptosis was triggered within 48-h treatment, without oxidative burst and modulation of the Bax to Bcl-2 ratio. When used as pre-treatments, these derivatives were also able to potentiate adriamycin and cisplatin toxicity in both cell lines. Thus, maleic anhydride derivatives may mediate apoptosis through a cell cycle blockage via inhibition of Cdc25. This class of inhibitors may present potential interest in therapeutic strategies against cancer. (C) 2007 Elsevier Inc. All rights reserved.
机译:双重特异性磷酸酶Cdc25通过激活Cdk /细胞周期蛋白复合物的激酶在细胞周期调节中起关键作用。在哺乳动物中已经鉴定出三种Cdc25同工型(A,B和C)。 Cdc25A和B显示出致癌特性,并在不同的肿瘤中过表达。因此,Cdc25磷酸酶是治疗策略的诱人靶标。已经合成了带有可变大小的脂肪酸链的新型马来酸酐衍生物,并使用体外测定法测试了其对Cdc25抑制的潜力。我们报告了对乳腺癌细胞(MCF7)及其对长春新碱(Vcr-R)具有抗性的无效,中度和有效抑制剂的生物活性。最有效的化合物在细胞周期的G0 / G1期诱导Cdk2抑制和积累。而且,在48小时的治疗中触发了细胞凋亡,而没有氧化爆发和Bax与Bcl-2比例的调节。当用作预处理剂时,这些衍生物还能够增强两种细胞系中的阿霉素和顺铂毒性。因此,马来酸酐衍生物可以通过抑制Cdc25通过细胞周期阻断来介导凋亡。这类抑制剂可能对癌症的治疗策略产生潜在的兴趣。 (C)2007 Elsevier Inc.保留所有权利。

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