Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies

被引:117
作者
Qian, Xiaozhong
LaRochelle, William J.
Ara, Gulshan
Wu, Frank
Petersen, Kamille Dumong
Thougaard, Annemette
Sehested, Maxwell
Lichenstein, Henri S.
Jeffers, Michael
机构
[1] CuraGen Corp, Branford, CT 06405 USA
[2] TopoTarget, Copenhagen, Denmark
关键词
D O I
10.1158/1535-7163.MCT-06-0111
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Histone deacetylase inhibitors represent a promising new class of anticancer agents. In the current investigation, we examined the activity of PXD101, a potent histone deacetylase inhibitor, used alone or in combination with clinically relevant chemotherapeutics (docetaxel, paclitaxel, and carboplatin), in preclinical in vitro and in vivo models of ovarian cancer. In vitro activity was examined in ovarian cancer and multidrug-resistant cell lines grown in monolayer culture, and in primary clinical ovarian cancer specimens grown in three-dimensional organoid culture. PXD101 was found to inhibit in vitro cancer cell growth at sub- to low micromolar IC50 potency, exhibited synergistic activity when used in combination with relevant chemotherapeutics, and effectively inhibited the growth of multidrug-resistant cells. In vivo, PXD101 displayed single-agent antitumor activity on human A2780 ovarian cancer s.c. xenografts which was enhanced via combination therapy with carboplatin. In support of these findings, PXD101 was shown to increase the acetylation of alpha-tubulin induced by docetaxel and the phosphorylation of H2AX induced by carboplatin. Taken together, these results support the clinical evaluation of PXD101 used alone or in combination therapy for the treatment of ovarian cancer.
引用
收藏
页码:2086 / 2095
页数:10
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