A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies.

Abstract

Polo-like kinase1 (PLK1) belongs to the family of serine/threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in a variety of human leukemia cell lines (n=20), as well as, freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n=50) and acute lymphoblastic leukemia (n=15) compared with bone marrow mononuclear cells from healthy volunteers (n=13) (acute myelogenous leukemia, P=0.016; acute lymphoblastic leukemia, P=0.008), as measured by real-time RT-PCR. Downregulation of PLK1 by a small interfering RNA in NB4 acute myelogenous leukemia cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound-induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Pre-treatment of cells with the caspase inhibitor Z-VAD-FMK attenuated the action of GW843682X in leukemia cells, indicating the involvement of the caspase pathway in the PLK1 inhibitor-mediated apoptosis. Furthermore, we found that the PLK1 inhibitor synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulin-depolymerizing agent vincristine. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia.

• Authors: T Ikezoe, J Yang, C Nishioka, Y Takezaki, T Tasaka, K Togitani, H P Koeffler, A Yokoyama
• Journal: Leukemia (Leukemia) Vol. 23 Issue 9 Pg. 1564-76 (Sep 2009) ISSN: 1476-5551 [Electronic] England
• PMID: 19421227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide
• Benzimidazoles
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• RNA, Messenger
• Thiophenes
• Vincristine
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• G2 Phase (drug effects)
• Humans
• Leukemia (drug therapy, enzymology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics)
• RNA, Messenger (analysis)
• Thiophenes (pharmacology)
• Vincristine (pharmacology)