Specific inhibition of basal mitogen-activated protein kinases and phosphatidylinositol 3 kinase activities in leukemia cells: a possible therapeutic role for the kinase inhibitors

• Published in: Experimental hematology Vol. 36; no. 1; pp. 28 - 36
• Main Authors: Champelovier, Pierre, El Atifi, Michèle, Pautre, Virginie, Rostaing, Béatrice, Berger, François, Seigneurin, Daniel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 2008; Elsevier
• Subjects: 1-Phosphatidylinositol 3-Kinase; Advanced Basic Science; Anthracenes; Anthracenes - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry, Molecular Biology; Cell Cycle; Cell Cycle - drug effects; Cell Cycle Proteins; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cell Differentiation; Cell Differentiation - drug effects; Cell Division; Cell Division - drug effects; Cell Line, Tumor; Cell Line, Tumor - drug effects; Cell Line, Tumor - enzymology; Chromones; Chromones - pharmacology; Drug Screening Assays, Antitumor; Drug Synergism; Flavonoids; Flavonoids - pharmacology; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Leukemic - drug effects; Hematology, Oncology and Palliative Medicine; HL-60 Cells; HL-60 Cells - drug effects; HL-60 Cells - enzymology; Humans; Imidazoles; Imidazoles - pharmacology; Leukemia; Leukemia - drug therapy; Leukemia - enzymology; Leukemia - pathology; Life Sciences; MAP Kinase Signaling System; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Monocytes; Monocytes - drug effects; Monocytes - enzymology; Morpholines; Morpholines - pharmacology; Neoplasm Proteins; Neoplasm Proteins - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein Kinase Inhibitors; Protein Kinase Inhibitors - pharmacology; Pyridines; Pyridines - pharmacology; U937 Cells; U937 Cells - drug effects; U937 Cells - enzymology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2007.08.027

Objective The roles of phosphatidylinositol 3 (PI3K) and mitogen-activated protein kinases (MAPK) have been widely studied in terms of the differentiation process induced by several drugs (phorbol ester, vitamin D-3, retinoic acid, etc.), but their exact functions in leukemic cells' phenotype and their potential therapeutic role remain incompletely clarified. Materials and Methods In order to investigate this query, leukemia cells were cultured in presence of kinase inhibitors (KIs). Proliferation, apoptosis, and differentiation were analyzed at the cellular and molecular levels, using flow cytometry and reverse transcriptase quantitative polymerase chain reaction. Results SB203580, a P38 MAPK inhibitor, had no effect on cell proliferation, whereas LY294002, a PI3K inhibitor, and PD098059, a selective inhibitor of mitogen-activated extracellular regulated kinase (MEK) phosphorylation, arrested cells in G0 /G1 . However, LY294002 and PD098059 acted using different mechanisms: LY294002 decreased the expression of phosphorylated S6RP, whereas PD098059 increased P21/waf1 antigen expression. SP600125, an inhibitor of N-terminal c-jun kinases, arrested cells in G2 and induced an endoreplicative process. SP600125 increased p21 at both the mRNA and protein levels. G2 blockage is dependent on the PI3K pathway and the endoreplicative process is dependent on the PI3K and extracellular regulated kinase (ERK) pathways and mRNA synthesis. On the other hand, PD098059 potentiated the apoptotic process induced by either SP600125 or LY294002. Modulation of the expression of CD11, CD15, CD18, and CD54 was cell-dependent. Conclusion Our results suggest that KIs modulate proliferation of leukemia cells and that the MEK/ERK inhibitor, PD098059, in combination with either SP600125 or LY294002, could have clinical value.