Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

A M Martelli; V Papa; P L Tazzari; F Ricci; C Evangelisti; F Chiarini; C Grimaldi; A Cappellini; G Martinelli; E Ottaviani; P Pagliaro; S Horn; J Bäsecke; L H Lindner; H Eibl; J A McCubrey

doi:10.1038/leu.2010.32

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

Leukemia. 2010 Apr;24(4):687-98. doi: 10.1038/leu.2010.32. Epub 2010 Mar 4.

Authors

A M Martelli¹, V Papa, P L Tazzari, F Ricci, C Evangelisti, F Chiarini, C Grimaldi, A Cappellini, G Martinelli, E Ottaviani, P Pagliaro, S Horn, J Bäsecke, L H Lindner, H Eibl, J A McCubrey

Affiliation

¹ Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy. alberto.martelli@gmail.it

PMID: 20200557
DOI: 10.1038/leu.2010.32

Abstract

Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34(+) leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34(+) CD38(Low/Neg) CD123(+)) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Blotting, Western
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Erucic Acids / pharmacology*
Flow Cytometry
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
MAP Kinase Kinase 4 / metabolism*
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylcholine / analogs & derivatives*
Phosphorylcholine / pharmacology
Precursor Cells, B-Lymphoid / drug effects*
Precursor Cells, B-Lymphoid / metabolism
Protein Phosphatase 2 / antagonists & inhibitors
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction

Substances

Erucic Acids
Phosphoinositide-3 Kinase Inhibitors
RNA, Messenger
erucylphosphohomocholine ErPC3
Phosphorylcholine
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase 4
Protein Phosphatase 2

Grants and funding

R01098195/PHS HHS/United States