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Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth.

AbstractPURPOSE:
The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457.
EXPERIMENTAL DESIGN:
We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models.
RESULTS:
In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values<0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P <or= 0.03). Proliferating cell nuclear antigen immunohistochemistry revealed that MK-0457 alone and in combination with docetaxel significantly reduced cellular proliferation (P values<0.001). Compared with controls, treatment with MK-0457 alone and in combination with docetaxel also significantly increased tumor cell apoptosis by approximately 3-fold (P<0.01). Remarkably, compared with docetaxel monotherapy, MK-0457 combined with docetaxel resulted in significantly increased tumor cell apoptosis.
CONCLUSIONS:
Aurora kinase inhibition significantly reduces tumor burden and cell proliferation and increases tumor cell apoptosis in this preclinical orthotopic model of ovarian cancer. The role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.
AuthorsYvonne G Lin, Anand Immaneni, William M Merritt, Lingegowda S Mangala, Seung Wook Kim, Mian M K Shahzad, Yvonne T M Tsang, Guillermo N Armaiz-Pena, Chunhua Lu, Aparna A Kamat, Liz Y Han, Whitney A Spannuth, Alpa M Nick, Charles N Landen Jr, Kwong K Wong, Michael J Gray, Robert L Coleman, Diane C Bodurka, William R Brinkley, Anil K Sood
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 17 Pg. 5437-46 (Sep 1 2008) ISSN: 1078-0432 [Print] United States
PMID18765535 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Piperazines
  • Taxoids
  • docetaxel
  • VX680
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Apoptosis (drug effects)
  • Aurora Kinases
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Enzyme Inhibitors (therapeutic use)
  • Female
  • Humans
  • Mice
  • Ovarian Neoplasms (drug therapy)
  • Piperazines (therapeutic use)
  • Protein-Serine-Threonine Kinases (antagonists & inhibitors)
  • Taxoids (administration & dosage)
  • Xenograft Model Antitumor Assays

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