Synergistic effects of suberoylanilide hydroxamic acid combined with             cisplatin causing cell cycle arrest independent apoptosis in platinum-resistant             ovarian cancer cells.
Histone deacetylase inhibitors (HDACIs) belong to an emerging class of anticancer             compounds. It is increasingly recognized that their unique and complementary mode             of action make HDACIs valuable agents in augmenting the cytotoxicity of conventional             chemotherapeutics. We examined the potential for combined use of an approved HDACI,             suberoylanilide hydroxamic acid (SAHA), with cisplatin (Cddp) in platinum-resistant             ovarian cancer cells, OVCAR-3 and SKOV-3. The nature of the drug interaction following             combinatory therapy was assessed using median effect analysis. We found that SAHA             acted synergistically with Cddp over a wide range of concentrations in both cell             types, resulting in favorable dose reductions of both compounds. In particular,             in the more Cddp-resistant SKOV-3 cells, more than 8-fold dose reduction of Cddp             was achieved with the simultaneous use of SAHA and Cddp as compared to the dose             required to elicit similar cell kill effects using Cddp alone. More importantly,             therapeutic selectivity for ovarian cancer cells over normal fibroblast cells             were maintained with the combinatorial therapy. We further observed that the augmentation             of Cddp-induced cell death was mediated by the net increase in apoptosis and was             independent of cell cycle arrest. Overall, concurrent application of SAHA and             Cddp yielded the most favorable cell kill, indicating that this combination is             promising for treatment of platinum-resistant ovarian tumors.
Department of Pharmacy, National University of Singapore, Singapore                     117543, Republic of Singapore.
Pei-Shi
PS
Ong
Xin-Qiao
XQ
Wang
Hai-Shu
HS
Lin
Sui-Yung
SY
Chan
Paul C
PC
Ho
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000473:pathology*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D002945:Cisplatin