Therapeutic polo-like kinase 1 inhibition results in mitotic arrest and subsequent cell death of blasts in the bone marrow of AML patients and has similar effects in non-neoplastic cell lines.

Abstract

Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.

• Authors: Claudia Münch, Diana Dragoi, Anna-Verena Frey, Katja Thurig, Michael Lübbert, Ralph Wäsch, Lioudmila Bogatyreva, Dieter Hauschke, Silke Lassmann, Martin Werner, Annette M May
• Journal: Leukemia research (Leuk Res) Vol. 39 Issue 4 Pg. 462-70 (Apr 2015) ISSN: 1873-5835 [Electronic] England
• PMID: 25697066 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antimitotic Agents
• BI 2536
• BI 6727
• Cell Cycle Proteins
• Proto-Oncogene Proteins
• Pteridines
• RNA, Messenger
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Aged
• Aged, 80 and over
• Antimitotic Agents (pharmacology)
• Apoptosis (drug effects)
• Blast Crisis (drug therapy, enzymology, pathology)
• Blotting, Western
• Bone Marrow (drug effects, enzymology, pathology)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Proliferation (drug effects)
• Female
• Humans
• Immunoenzyme Techniques
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Male
• Mitosis (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Pteridines (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured