CDC25 Inhibition in Acute Myeloid Leukemia-A Study of Patient Heterogeneity and the Effects of Different Inhibitors

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2017 Mar 14

PMID 28287460

Citations 5

Authors

Annette K Brenner

Hakon Reikvam

Kristin Paulsen Rye

Karen Marie Hagen

Antonio Lavecchia

Oystein Bruserud

Affiliations

Soon will be listed here.

Abstract

Cell division cycle 25 (CDC25) protein phosphatases regulate cell cycle progression through the activation of cyclin-dependent kinases (CDKs), but they are also involved in chromatin modulation and transcriptional regulation. CDC25 inhibition is regarded as a possible therapeutic strategy for the treatment of human malignancies, including acute myeloid leukemia (AML). We investigated the in vitro effects of CDC25 inhibitors on primary human AML cells derived from 79 unselected patients in suspension cultures. Both the previously well-characterized CDC25 inhibitor NSC95397, as well as five other inhibitors (BN82002 and the novel small molecular compounds ALX1, ALX2, ALX3, and ALX4), only exhibited antiproliferative effects for a subset of patients when tested alone. These antiproliferative effects showed associations with differences in genetic abnormalities and/or AML cell differentiation. However, the responders to CDC25 inhibition could be identified by analysis of global gene expression profiles. The differentially expressed genes were associated with the cytoskeleton, microtubules, and cell signaling. The constitutive release of 28 soluble mediators showed a wide variation among patients and this variation was maintained in the presence of CDC25 inhibition. Finally, NSC95397 had no or only minimal effects on AML cell viability. In conclusion, CDC25 inhibition has antiproliferative effects on primary human AML cells for a subset of patients, and these patients can be identified by gene expression profiling.

Citing Articles

Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine.

Dakilah I, Harb A, Abu-Gharbieh E, El-Huneidi W, Taneera J, Hamoudi R Front Pharmacol. 2024; 15:1324001.

PMID: 38313315 PMC: 10834672. DOI: 10.3389/fphar.2024.1324001.

Shikonin and Juglone Inhibit Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa).

Sulyman A, Fulcher J, Crossley S, Fatokun A, Olorunniji F BioTech (Basel). 2023; 12(3).

PMID: 37754203 PMC: 10526854. DOI: 10.3390/biotech12030059.

Synthesis, anticancer activity, and molecular modeling of 1,4-naphthoquinones that inhibit MKK7 and Cdc25.

Schepetkin I, Karpenko A, Khlebnikov A, Shibinska M, Levandovskiy I, Kirpotina L Eur J Med Chem. 2019; 183:111719.

PMID: 31563013 PMC: 6925601. DOI: 10.1016/j.ejmech.2019.111719.

Special Issue: Kinase inhibitors.

Koch P, Laufer S Molecules. 2018; 23(7).

PMID: 30037125 PMC: 6099724. DOI: 10.3390/molecules23071818.

Resistance to the Antiproliferative In Vitro Effect of PI3K-Akt-mTOR Inhibition in Primary Human Acute Myeloid Leukemia Cells Is Associated with Altered Cell Metabolism.

Nepstad I, Reikvam H, Brenner A, Bruserud O, Hatfield K Int J Mol Sci. 2018; 19(2).

PMID: 29382066 PMC: 5855604. DOI: 10.3390/ijms19020382.

References

Donzelli M, Squatrito M, Ganoth D, Hershko A, Pagano M, Draetta G . Dual mode of degradation of Cdc25 A phosphatase. EMBO J. 2002; 21(18):4875-84. PMC: 126287. DOI: 10.1093/emboj/cdf491. View

Estey E, Dohner H . Acute myeloid leukaemia. Lancet. 2006; 368(9550):1894-907. DOI: 10.1016/S0140-6736(06)69780-8. View

Lazo J, Nemoto K, Pestell K, Cooley K, Southwick E, Mitchell D . Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors. Mol Pharmacol. 2002; 61(4):720-8. DOI: 10.1124/mol.61.4.720. View

de Jonge H, Valk P, de Bont E, Schuringa J, Ossenkoppele G, Vellenga E . Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. Haematologica. 2011; 96(9):1310-7. PMC: 3166101. DOI: 10.3324/haematol.2011.040592. View

Karlsson C, Katich S, Hagting A, Hoffmann I, Pines J . Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J Cell Biol. 1999; 146(3):573-84. PMC: 2150562. DOI: 10.1083/jcb.146.3.573. View

Damm F, Heuser M, Morgan M, Wagner K, Gorlich K, Grosshennig A . Integrative prognostic risk score in acute myeloid leukemia with normal karyotype. Blood. 2011; 117(17):4561-8. DOI: 10.1182/blood-2010-08-303479. View

Pu L, Amoscato A, Bier M, Lazo J . Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 6-chloro-7-[corrected](2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem. 2002; 277(49):46877-85. DOI: 10.1074/jbc.M207902200. View

Lavecchia A, Coluccia A, Di Giovanni C, Novellino E . Cdc25B phosphatase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anticancer Agents Med Chem. 2008; 8(8):843-56. DOI: 10.2174/187152008786847783. View

Didier C, Cavelier C, Quaranta M, Galcera M, Demur C, Laurent G . G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress. Oncogene. 2008; 27(27):3811-20. DOI: 10.1038/sj.onc.1211041. View

10.

Perwitasari O, Torrecilhas A, Yan X, Johnson S, White C, Tompkins S . Targeting cell division cycle 25 homolog B to regulate influenza virus replication. J Virol. 2013; 87(24):13775-84. PMC: 3838213. DOI: 10.1128/JVI.01509-13. View

11.

Brenner A, Reikvam H, Lavecchia A, Bruserud O . 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(11):18414-47. PMC: 6270710. DOI: 10.3390/molecules191118414. View

12.

Bruserud O, Gjertsen B, FOSS B, Huang T . New strategies in the treatment of acute myelogenous leukemia (AML): in vitro culture of aml cells--the present use in experimental studies and the possible importance for future therapeutic approaches. Stem Cells. 2001; 19(1):1-11. DOI: 10.1634/stemcells.19-1-1. View

13.

Kar S, Wang M, Carr B . 2-Methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis. Cancer Chemother Pharmacol. 2008; 62(5):831-40. DOI: 10.1007/s00280-007-0670-x. View

14.

Hasserjian R . Acute myeloid leukemia: advances in diagnosis and classification. Int J Lab Hematol. 2013; 35(3):358-66. DOI: 10.1111/ijlh.12081. View

15.

Keefer M, Bonnez W, Roberts Jr N, Dolin R, Reichman R . Human immunodeficiency virus (HIV-1) gp160-specific lymphocyte proliferative responses of mononuclear leukocytes from HIV-1 recombinant gp160 vaccine recipients. J Infect Dis. 1991; 163(3):448-53. DOI: 10.1093/infdis/163.3.448. View

16.

Lavecchia A, Di Giovanni C, Pesapane A, Montuori N, Ragno P, Martucci N . Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening. J Med Chem. 2012; 55(9):4142-58. DOI: 10.1021/jm201624h. View

17.

Lee G, White L, Hurov K, Stappenbeck T, Piwnica-Worms H . Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion. Proc Natl Acad Sci U S A. 2009; 106(12):4701-6. PMC: 2660721. DOI: 10.1073/pnas.0900751106. View

18.

Huber-Villaume S, Revelant G, Sibille E, Philippot S, Morabito A, Dunand S . 2-(Thienothiazolylimino)-1,3-thiazolidin-4-ones inhibit cell division cycle 25 A phosphatase. Bioorg Med Chem. 2016; 24(13):2920-2928. DOI: 10.1016/j.bmc.2016.04.063. View

19.

Fernandez-Vidal A, Ysebaert L, Didier C, Betous R, De Toni F, Prade-Houdellier N . Cell adhesion regulates CDC25A expression and proliferation in acute myeloid leukemia. Cancer Res. 2006; 66(14):7128-35. DOI: 10.1158/0008-5472.CAN-05-2552. View

20.

Oyan A, Bo T, Jonassen I, Ulvestad E, Gjertsen B, Kalland K . CD34 expression in native human acute myelogenous leukemia blasts: differences in CD34 membrane molecule expression are associated with different gene expression profiles. Cytometry B Clin Cytom. 2005; 64(1):18-27. DOI: 10.1002/cyto.b.20044. View