Abstract 5450: Enhanced cytotoxicity of carboplatin and paclitaxel (CP) by vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor, in melanoma cell lines

Abstract

Abstract Background: CP is the mainstay of therapy in NSCLC and ovarian cancer and recently gained wide use in melanoma. Vorinostat (SAHA) is a histone deacetylase inhibitor that affects tumor growth via histone and non-histone targets. Combination of CP + SAHA was safe and showed impressive activity in NSCLC in a Phase I trial. We hypothesized that SAHA will enhance CP cytotoxicity in melanoma cells. Methods: IC50 values in A375 and FEMX-1 human melanoma cells were determined using MTS after incubation for 72 h. Carboplatin and paclitaxel were combined at their IC50 ratio and considered a single drug. Schedules were: a) 72 h concomitant SAHA and CP; b) 48 h SAHA + 48 h rest + 72 h CP; c) 96 h SAHA + 72 h CP; d) 96 h SAHA + 72 h CP and SAHA. SAHA was used at 1 µM or the single agent IC50. CP was used at dilutions of the combined IC50. Experiments were repeated 3 times. Results: SAHA displayed single-agent activity at clinically achievable concentrations (IC50 1.48 µM for FEMX-1, 2.45 µM for A375). Addition of SAHA enhanced cytotoxicity of CP. Concomitant treatment for 72 h led to >50% cell kill even at 50% of CP IC50. Pretreatment for 48 h followed by 48 h of rest and 72 hr CP demonstrated enhancement that was less pronounced, suggesting that the effect of SAHA may be partly reversible. SAHA pretreatment for 96 h followed by SAHA+CP for 72 h was most effective with >90% cell kill even at CP as low as 25% of IC50. Higher doses of SAHA gave consistently greater effects. Conclusion: Treatment with SAHA enhances CP cytotoxicity in melanoma cells at all doses and schedules evaluated, but SAHA pretreatment followed by the 3-drug combination had the highest activity. Our results support the clinical evaluation of the combination of SAHA and CP in metastatic melanoma in a Phase II trial. Support: Hillman Foundation for Innovative Cancer Research; NCI-CTEPExp. % Survival (+/− Standard Error) 0 - 48 h48 - 168 h96-168 h SAHASAHACP 0CP 0.25CP 0.5CP 0.751--10076.8 (+/− 2.5)72.6 (+/− 1.5)67.9 (+/− 4.4)2-1 µM99.8 (+/− 7.1)67.5 (+/− 4.8)52.7 (+/− 2.3)40.2 (+/− 3.2)3-1.48 µM76.5 (+/− 6.6)60.6 (+/− 3.6)40.2 (+/− 0.7)35.9 (+/− 0.7)41 µM-78.5 (+/− 13.3)56.7 (+/− 9.7)42.2 (+/− 13.4)23.9 (+/− 6.1)51 µM1 µM50.7 (+/− 9.8)25.4 (+/− 4.9)19.7 (+/− 4.3)13.1 (+/− 1.9)61.48 µM-33.1 (+/− 6.1)18.4 (+/− 2.2)11.6 (+/− 1.4)7.2 (+/− 1.2)71.48 µM1.48 µM15.0 (+/− 2.5)8.1 (+/− 0.9)6.1 (+/− 0.2)5.9 (+/− 1.0) Results for FEMX-1 represented as % cells surviving after treatment as indicated. CP was added at dilutions of IC50 (0, 0.25, 0.5 and 0.75). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5450.