HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo.

Abstract
Aurora kinases play a critical role in regulating mitosis and cell division, and their overexpression has been implicated in the survival and proliferation of human cancer. In this study, we report the in vitro and in vivo activities of AZD1152, a compound that has selectivity for aurora B kinase, in acute myeloid leukemia (AML) cell lines, primary AML samples, and cord blood cells. AZD1152 exerted antiproliferative or cytotoxic effects in all cell lines studied, inhibited the phosphorylation of histone H3 (pHis H3) on Ser10 in a dose-dependent manner, and resulted in cells with >4N DNA content. THP-1 cells treated with AZD1152 accumulated in a state of polyploidy and showed a senescent response to the drug, in contrast to the apoptotic response seen in other cell lines. Accordingly, AZD1152 profoundly affected the growth of AML cell lines and primary AML in an in vivo xenotransplantation model. However, concentration-dependent effects on cell growth, apoptosis, and cell cycle progression were also observed when human cord blood and primary lineage-negative stem and progenitor cells were analyzed in vitro and in vivo. These data suggest that the inhibition of aurora B kinase may be a useful therapeutic strategy in the treatment of AML and that further exploration of dosing and treatment schedules is warranted in clinical trials.
AuthorsAdedayo Oke, Daniel Pearce, Robert W Wilkinson, Claire Crafter, Rajesh Odedra, Jamie Cavenagh, Jude Fitzgibbon, Andrew T Lister, Simon Joel, Dominique Bonnet
JournalCancer research (Cancer Res) Vol. 69 Issue 10 Pg. 4150-8 (May 15 2009) ISSN: 1538-7445 [Electronic] United States
PMID19366807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • Annexin A5
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Organophosphates
  • Quinazolines
  • AURKB protein, human
  • Aurkb protein, mouse
  • Aurora Kinase B
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
Topics
  • Animals
  • Annexin A5 (metabolism)
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • HL-60 Cells (drug effects)
  • Hematopoietic Stem Cells (cytology, drug effects)
  • Humans
  • Leukemia, Myeloid, Acute (drug therapy, pathology)
  • Mice
  • Organophosphates (pharmacology)
  • Protein Serine-Threonine Kinases (antagonists & inhibitors)
  • Quinazolines (pharmacology)
  • U937 Cells (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: