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Abstract
BackgroundHistone deacetylase inhibitors (HDACi) exert multiple cytotoxic actions on cancer cells. Currently, different synthetic HDACi are in clinical use or clinical trials; nevertheless, since both pro-invasive and anti-invasive activities have been described, there is some controversy about the effect of HDACi on melanoma cells.MethodsMatrigel and Collagen invasion assays were performed to evaluate the effect of several HDACi (Butyrate, Trichostatin A, Valproic acid and Vorinostat) on two human melanoma cell line invasion (A375 and HT-144). The expression of N- and E-Cadherin and the activity of the RhoA GTPase were analyzed to elucidate the mechanisms involved in the HDACi activity.ResultsHDACi showed a pro-invasive effect on melanoma cells in vitro. This effect was accompanied by an up-regulation of N-cadherin expression and an inhibition of RhoA activity. Moreover, the down-regulation of N-cadherin through blocking antibodies or siRNA abrogated the pro-invasive effect of the HDACi and, additionally, the inhibition of the Rho/ROCK pathway led to an increase of melanoma cell invasion similar to that observed with the HDACi treatments.ConclusionThese results suggest a role of N-cadherin and RhoA in HDACi induced invasion and call into question the suitability of some HDACi as antitumor agents for melanoma patients.
Highlights
Histone deacetylase inhibitors (HDACi) exert multiple cytotoxic actions on cancer cells
HDACi sensitivity assay Cells were treated for 24 h with varying concentrations of Butyrate (1, 2, 4, 8 and 16 mM), Trichostatin A (TSA) (50, 100, 200, 300 and 400 nM), Valproic acid (0.5, 1, 2, 4 and 8 mM) and Vorinostat (1.5, 3, 6, 12 and 24 μM)
HDACi induce melanoma invasion in Matrigel and type I collagen In order to elucidate the role of HDACi in the invasive ability of melanoma cells, we have tested the effect of four different HDACi on A375 and HT-144 melanoma cell lines using Matrigel and type I collagen invasion assays
Summary
Histone deacetylase inhibitors (HDACi) exert multiple cytotoxic actions on cancer cells. In a phase I/II clinical trial of Valproic acid in combination with Topoisomerase I inhibitor, Karenitecin, 47 % of patients had stable disease with median progression-free survival of 10.3 weeks versus 34 % with stable disease with median progression-free survival of 7.9 weeks shown in patients on a previous phase II study with Karenitecin as a single agent [10]. In another phase I study with the HDACi MS-275 disease stabilization and partial remission were observed in patients with melanoma and other solid tumors [11]. No responses were shown under RECIST criteria [12]
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