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


METHODS
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.
Lin
Yvonne G
YG
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Immaneni
Anand
A
Merritt
William M
WM
Mangala
Lingegowda S
LS
Kim
Seung Wook
SW
Shahzad
Mian M K
MM
Tsang
Yvonne T M
YT
Armaiz-Pena
Guillermo N
GN
Lu
Chunhua
C
Kamat
Aparna A
AA
Han
Liz Y
LY
Spannuth
Whitney A
WA
Nick
Alpa M
AM
Landen
Charles N
CN
Wong
Kwong K
KK
Gray
Michael J
MJ
Coleman
Robert L
RL
Bodurka
Diane C
DC
Brinkley
William R
WR
Sood
Anil K
AK