Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors.

Abstract

Mnk kinases regulate the phosphorylation and activation of the eukaryotic initiation factor 4E (eIF4E), a protein that plays key roles in the initiation of messenger RNA translation and whose activity is critical for various cellular functions. eIF4E is deregulated in acute myeloid leukemia (AML), and its aberrant activity contributes to leukemogenesis. We determined whether cercosporamide, an antifungal agent that was recently shown to act as a unique Mnk inhibitor, exhibits antileukemic properties. Treatment of AML cells with cercosporamide resulted in a dose-dependent suppression of eIF4E phosphorylation. Such suppression of Mnk kinase activity and eIF4E phosphorylation by cercosporamide resulted in dose-dependent suppressive effects on primitive leukemic progenitors (CFU-L) from AML patients and enhanced the antileukemic properties of cytarabine (Ara-C) or mammalian target of rapamycin (mTOR) complex 1 inhibition. Similarly, the combination of cercosporamide with cytarabine resulted in enhanced antileukemic responses in a xenograft mouse model in vivo. Altogether, this work demonstrates that the unique Mnk inhibitor cercosporamide suppresses phosphorylation of eIF4E and exhibits antileukemic effects, in support of future clinical-translational efforts involving combinations of Mnk inhibitors with cytarabine and/or mTOR inhibitors for the treatment of AML.

• Authors: Jessica K Altman, Amy Szilard, Bruce W Konicek, Philip W Iversen, Barbara Kroczynska, Heather Glaser, Antonella Sassano, Eliza Vakana, Jeremy R Graff, Leonidas C Platanias
• Journal: Blood (Blood) Vol. 121 Issue 18 Pg. 3675-81 (May 02 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23509154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzofurans
• Cation Transport Proteins
• Protein Kinase Inhibitors
• cercosporamide
• Adenosine Triphosphatases
• ATP7A protein, human
• Copper-Transporting ATPases

Topics

• Adenosine Triphosphatases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (therapeutic use)
• Benzofurans (therapeutic use)
• Cation Transport Proteins (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Copper-Transporting ATPases
• Down-Regulation (drug effects)
• Humans
• K562 Cells
• Leukemia, Myeloid, Acute (drug therapy)
• Mice
• Neoplastic Stem Cells (drug effects)
• Protein Kinase Inhibitors (therapeutic use)
• U937 Cells
• Xenograft Model Antitumor Assays