Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies.
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 IC(50) 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.
Qian
Xiaozhong
X
CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA.
LaRochelle
William J
WJ
Ara
Gulshan
G
Wu
Frank
F
Petersen
Kamille Dumong
KD
Thougaard
Annemette
A
Sehested
Maxwell
M
Lichenstein
Henri S
HS
Jeffers
Michael
M
D000107:Acetylation; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D013449:Sulfonamides; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D016190:Carboplatin; C487081:belinostat