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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)687-698
Number of pages12
JournalLeukemia
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2010

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Acute Myeloid Leukemia
Apoptosis
Protein Phosphatase 2
Cell Line
Aldehyde Dehydrogenase
G2 Phase
Caspase 3
Cell Division
Antineoplastic Agents
Small Interfering RNA
Signal Transduction
Cell Cycle
Leukemia
Cell Death
Therapeutics
Down-Regulation
Cell Membrane
Pharmacology
Peptides
Survival

Keywords

  • Apoptosis
  • Caspases
  • Leukemia-initiating cells
  • MEK/ERK signaling
  • PP2A

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK-and PP2A-dependent mechanisms. / Martelli, A. M.; Papa, V.; Tazzari, P. L.; Ricci, F.; Evangelisti, C.; Chiarini, F.; Grimaldi, C.; Cappellini, A.; Martinelli, G.; Ottaviani, E.; Pagliaro, P.; Horn, S.; Bäsecke, J.; Lindner, L. H.; Eibl, H.; McCubrey, J. A.

In: Leukemia, Vol. 24, No. 4, 04.2010, p. 687-698.

Research output: Contribution to journalArticle

Martelli, AM, Papa, V, Tazzari, PL, Ricci, F, Evangelisti, C, Chiarini, F, Grimaldi, C, Cappellini, A, Martinelli, G, Ottaviani, E, Pagliaro, P, Horn, S, Bäsecke, J, Lindner, LH, Eibl, H & McCubrey, JA 2010, 'Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK-and PP2A-dependent mechanisms', Leukemia, vol. 24, no. 4, pp. 687-698. https://doi.org/10.1038/leu.2010.32
Martelli, A. M. ; Papa, V. ; Tazzari, P. L. ; Ricci, F. ; Evangelisti, C. ; Chiarini, F. ; Grimaldi, C. ; Cappellini, A. ; Martinelli, G. ; Ottaviani, E. ; Pagliaro, P. ; Horn, S. ; Bäsecke, J. ; Lindner, L. H. ; Eibl, H. ; McCubrey, J. A. / Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK-and PP2A-dependent mechanisms. In: Leukemia. 2010 ; Vol. 24, No. 4. pp. 687-698.
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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.",
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AU - Pagliaro, P.

AU - Horn, S.

AU - Bäsecke, J.

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