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Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia -- The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

机译:针对人类急性髓细胞白血病的细胞分裂周期25(CDC25)磷酸酶的治疗 - 通过抑制各种CDC25同种型靶向几种激酶的可能性

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摘要

The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment.
机译:细胞分裂周期25(CDC25)磷酸酶包括CDC25A,CDC25B和CDC25C。这三个分子是细胞周期中多个步骤的重要调节剂,包括各种细胞周期蛋白依赖性激酶(CDK)的激活。 CDC25似乎在几种人类恶性肿瘤的发展中起作用,包括急性髓细胞性白血病(AML)。因此,CDC25抑制被认为是一种可能的抗癌策略。首先,CDC25A的上调可以增强细胞增殖,其表达似乎受到PI3K-Akt-mTOR信号传导的控制,PI3K-Akt-mTOR信号传导可能介导人AML的化学耐药性。 CDC25A的丢失对于由恶性造血细胞的分化诱导引起的细胞周期停滞也很重要。其次,高CDC25B表达与抗PI3K-Akt-mTOR抑制剂在原代人AML细胞中的抗增殖作用有关,抑制这种亚型似乎可以通过对NFκB和p300的作用来减少AML细胞系的增殖。最后,CDC25C似乎对AML细胞的表型非常重要,至少对于一部分患者而言。许多已鉴定的CDC25抑制剂在三种CDC25同工型之间显示出交叉反应性。因此,通过使用这种交叉反应性抑制剂,有可能通过使用一种药物来抑制细胞周期进程甚至细胞质信号传导调控中的几种分子事件,包括几种CDK的激活。这样的组合策略可能在人类癌症治疗中将是一个优势。

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