Histone deacetylase inhibitors (HDAC-I) radiosensitizes two human thyroid cancer cell lines

PERONA, M; DAGROSA, MA; CASAL, M; PISAREV , M; JUVENAL, G

Paris

Congreso; 14th International Thyroid Congress; 2010

American Thyroid Association (ATA)

  Introduction: Thyroid cancer is the most common endocrine neoplasia. Surgical resection and radioactive iodine is an effective treatment for well-differentiated tumors. Histone deacetylase inhibitors (HDAC-I) are agents that cause hyperacetylation of histone proteins and as a consequence remodeling of chromatin structure. They can induce growth arrest, differentiation and apoptotic cell death in different tumor cells. The use of HDAC-I agents could be of utility to enhance the response to external radiation therapy of those thyroid cancers that are refractory to most conventional therapeutic treatments. Objective: To study the effect of HDAC-I as radiosensitizers for the treatment of thyroid cancer. Materials and methods: The human thyroid follicular (WRO) and papillary (TPC-1) carcinoma cell lines were seeded and incubated with increasing doses (0, 0.3, 0.5, 1 and 1.5 mM) of the HDAC-I sodium butirate (NaB) and valproic acid (VA) to evaluate cell proliferation and iodide uptake. Cells were irradiated with a 60Co ã-ray source (1 ± 5% Gy/min) and postirradiation survival was quantified with the colony formation assay. Survival fraction at 2 Gy (SF2) and dose modification factors (DMF is the ratio of survival for untreated cells and cells treated with the drug) at radiation doses that reduce survival at 37% and 10% (D37 and D10) were calculated. Results: Cell proliferation was not significantly suppressed after 24 hours of incubation with both drugs at all assayed doses. Iodide uptake was not modified after incubation with HDAC-I of both cell lines. SF2 was reduced from 68 ± 1.6 % in the control WRO cells to 42 ± 3.8 % (P<0.001) in NaB-treated cells. In TPC-1 SF2 was reduced from 32 ± 1.1 % in the control cells to 24 ± 0.8 % (P<0.01). In VA-treated cells SF2 was reduced from 69 ± 0.02 % in control WRO cells to 56 ± 0.01 % (P<0.01) and from 31 ± 2 % in control TPC-1 cells to 11 ± 1 % (P<0.01). DMF values at D37 and D10 were 1.6 and 1.2, and 1.5 and 1.2 in WRO and TPC-1 NaB-treated cells, respectively. For VA-treated cells, DMF were smaller with values of 1.3 and 1.1 for D37 and 1.2 and 1.1 for D10 in WRO and TPC-1, respectively. Conclusions: NaB was more efficient in sensitizing WRO cells than VA. VA was more effective in TPC-1 cells that also showed a higher intrinsic radiosensitivity. The combination of HDAC inhibitors and radiation resulted in a reduction of survival in both cell lines showing a synergistic effect.