Suberoylanilide hydroxamic acid partly reverses resistance to paclitaxel in human ovarian cancer cell lines.
OBJECTIVE
The purpose of this study was to determine whether the addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) to paclitaxel (PTX) can sensitize PTX-resistant human ovarian cancer cell lines (CABA-PTX and IGROV-PTX) in vitro.


METHODS
SAHA was studied in combination with paclitaxel in PTX-sensitive and PTX-resistant human ovarian cancer cell lines. Using cell proliferation analysis, immunofluorescence, and flow cytometric assays, we can determine whether the resistance was partly removed when the cells were treated with a combination of SAHA and PTX. Cells were also assayed for cytochrome c release. The levels of acetylated tubulin, β-tubulin, and HDAC6 were quantified by Western blots.


RESULTS
SAHA in combination with PTX led to a more pronounced inhibition of cell growth compared with PTX alone. In addition, the combined exposure to PTX and SAHA resulted in a marked arrest in the G2/M phase of the cell cycle and in a significant increase in the percentage of apoptotic cells. The expression of acetylated tubulin was dramatically increased by exposure to the combination of PTX and SAHA. These data paralleled the findings of an increased expression of HDAC6 in the presence of PTX in PTX-resistant cell lines.


CONCLUSIONS
The results of this study suggest the existence of a novel resistance mechanism based upon the upregulation of HDAC6 and that the histone deacetylase inhibitor SAHA holds promise to overcome PTX resistance in ovarian cancer cell lines.
Angelucci
Adriano
A
Department of Experimental Medicine, University of L'Aquila, Via Vetoio-Coppito 2, I-67100, L'Aquila, Italy.
Mari
Marianna
M
Millimaggi
Danilo
D
Giusti
Ilaria
I
Carta
Gaspare
G
Bologna
Mauro
M
Dolo
Vincenza
V
D000107:Acetylation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; D000077337:Vorinostat; D017239:Paclitaxel