In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer

被引:54
作者
Cooper, Amy L.
Greenberg, Victoria L.
Lancaster, Pamela S.
van Nagell, John R., Jr.
Zimmer, Stephen G.
Modesitt, Susan C.
机构
[1] Univ Virginia, Dept Obstet & Gynecol, Div Gynecol Oncol, Charlottesville, VA 22908 USA
[2] Univ Kentucky, Albert B Chandler Med Ctr, Div Gynecol Oncol, Lexington, KY 40506 USA
[3] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Div Gynecol Oncol, Lexington, KY 40506 USA
[4] Univ Kentucky, Dept Stat, Lexington, KY 40506 USA
关键词
histone deacetylase inhibitor; mouse ovarian cancer model; SAHA;
D O I
10.1016/j.ygyno.2006.09.011
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Objective. To determine effects of suberoylanilide hydroxamic acid (SAHA) with and without paclitaxel in ovarian cancer cells and a nude mouse model. Methods. Cell viability and apoptosis of ovarian cancer cells (2774) were measured following exposure to control, SAHA, paclitaxel, or SAHA in combination with paclitaxel. Nude mice were injected intraperitoneally (IP) with cancer cells and then groups received variable SAHA doses (25-100 mg/kg/day). In a second experiment, mice were inoculated with cancer and treated H? with vehicle injection, SAHA, paclitaxel, paclitaxel followed by SAHA, or SAHA followed by paclitaxel. Survival, tumor weight, and ascites were evaluated. Results. SAHA decreased viability and increased apoptosis similarly to paclitaxel, but the combination was not statistically significantly different from the single agents. The only significant difference in the SAHA alone mouse study was decreased survival in the 50 mg/kg/daily group. In the combination groups, SAHA followed by paclitaxel, paclitaxel alone, and paclitaxel followed by SAHA improved survival compared with control (p=0.0358, 0.0006, and 0.0001), but SAHA alone did not (p=0.524). The paclitaxel followed by SAHA group had improved survival compared to SAHA followed by paclitaxel (p=0.0002) but not compared to paclitaxel alone (p=0.166). Conclusions. In vitro, SAHA alone decreased viability and increased apoptosis similarly to paclitaxel. In vivo, paclitaxel followed by SAHA and paclitaxel alone increased survival compared with SAHA alone or SAHA followed by paclitaxel. This suggests adding SAHA to ovarian cancer chemotherapy could increase efficacy and that sequencing of agents is important. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:596 / 601
页数:6
相关论文
共 56 条
[1]   Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17) [J].
Amin, HM ;
Saeed, S ;
Alkan, S .
BRITISH JOURNAL OF HAEMATOLOGY, 2001, 115 (02) :287-297
[2]   Histone deacetylase inhibitors: From chromatin remodeling to experimental cancer therapeutics [J].
Arts, J ;
de Schepper, S ;
Van Emelen, K .
CURRENT MEDICINAL CHEMISTRY, 2003, 10 (22) :2343-2350
[3]   It's about time: Scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells [J].
Bevins, RL ;
Zimmer, SG .
CANCER RESEARCH, 2005, 65 (15) :6957-6966
[4]  
Butler LM, 2000, CANCER RES, V60, P5165
[5]  
Chobanian NH, 2004, ANTICANCER RES, V24, P539
[6]  
Cohen LA, 1999, ANTICANCER RES, V19, P4999
[7]  
DESIMONE CP, 2003, P AM ASSOC CANC RES, V44, P217
[8]  
DIETRICH G, 2006, GYNECOL ONCOL S1, V101, pS149
[9]  
DIGENNARO E, 2003, P AM ASSOC CANC RES, V44, pA3636
[10]   Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors [J].
Finnin M.S. ;
Donigian J.R. ;
Cohen A. ;
Richon V.M. ;
Rifkind R.A. ;
Marks P.A. ;
Breslow R. ;
Pavletich N.P. .
Nature, 1999, 401 (6749) :188-193