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.
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.
Section for Hematology, Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, 5021, Norway.
Annette K
AK
Brenner
Section for Hematology, Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, 5021, Norway.
Håkon
H
Reikvam
"Drug Discovery" Laboratory, Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy.
Antonio
A
Lavecchia
Section for Hematology, Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, 5021, Norway. oystein.bruserud@helse-bergen.no.
Øystein
Ø
Bruserud
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology; D014411:Neoplastic Stem Cells / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020687:cdc25 Phosphatases; C546842:MTOR protein, human; C517004:CDC25A protein, human; C517009:CDC25C protein, human