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Molecules 2014, 19(11), 18414-18447; doi:10.3390/molecules191118414

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

1
Section for Hematology, Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, 5021, Norway
2
Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
3
"Drug Discovery" Laboratory, Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy
*
Author to whom correspondence should be addressed.
Received: 15 August 2014 / Revised: 28 October 2014 / Accepted: 2 November 2014 / Published: 12 November 2014
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Abstract

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. View Full-Text
Keywords: CDC25; cell cycle; kinase; CDC25 inhibitors; anticancer agents; AML CDC25; cell cycle; kinase; CDC25 inhibitors; anticancer agents; AML
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MDPI and ACS Style

Brenner, A.K.; Reikvam, H.; Lavecchia, A.; Bruserud, Ø. 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. Molecules 2014, 19, 18414-18447.

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