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.