Lin Yvonne G, Immaneni Anand, Merritt William M, Mangala Lingegowda S, Kim Seung Wook, Shahzad Mian M K, Tsang Yvonne T M, Armaiz-Pena Guillermo N, Lu Chunhua, Kamat Aparna A, Han Liz Y, Spannuth Whitney A, Nick Alpa M, Landen Charles N, Wong Kwong K, Gray Michael J, Coleman Robert L, Bodurka Diane C, Brinkley William R, Sood Anil K
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2008 Sep 1;14(17):5437-46. doi: 10.1158/1078-0432.CCR-07-4922.
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.
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.
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.
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.
极光激酶家族在有丝分裂完整性和细胞周期中起关键作用。我们试图使用小分子泛极光激酶抑制剂MK-0457，在原位小鼠模型中确定抑制极光激酶对卵巢癌生长的影响。
我们使用体外和体内卵巢癌模型，研究了细胞周期调节作用，并确定了单独及与多西他赛联合使用时，极光激酶抑制的治疗效果。
对HeyA8和SKOV3ip1细胞进行的体外细胞毒性试验显示，与MK-0457联合使用时，多西他赛的细胞毒性增强了10倍以上。在使用磷酸化组蛋白H3状态确定体内剂量动力学后，对化疗敏感的HeyA8和SKOV3ip1以及化疗耐药的HeyA8-MDR和A2780-CP20模型进行的治疗实验表明，与对照组相比，单独抑制极光激酶可显著降低肿瘤负荷（P值<0.01）。与单独使用多西他赛相比，联合使用多西他赛治疗可显著改善肿瘤生长的抑制效果（P≤0.03）。增殖细胞核抗原免疫组化显示，单独使用MK-0457以及与多西他赛联合使用时，均可显著降低细胞增殖（P值<0.001）。与对照组相比，单独使用MK-0457以及与多西他赛联合使用时，肿瘤细胞凋亡也显著增加了约3倍（P<0.01）。值得注意的是，与多西他赛单药治疗相比，MK-0457与多西他赛联合使用可显著增加肿瘤细胞凋亡。
在该卵巢癌临床前原位模型中，抑制极光激酶可显著降低肿瘤负荷、减少细胞增殖并增加肿瘤细胞凋亡。极光激酶抑制在卵巢癌中的作用值得在临床试验中进一步研究。
