In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer.
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 IP 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.
Cooper
Amy L
AL
Division of Gynecologic Oncology, University of Kentucky Chandler Medical Center, Lexington, KY, USA.
Greenberg
Victoria L
VL
Lancaster
Pamela S
PS
van Nagell
John R
JR
Zimmer
Stephen G
SG
Modesitt
Susan C
SC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D017239:Paclitaxel