Evodiamine in combination with histone deacetylase inhibitors has synergistic cytotoxicity in thyroid carcinoma cells.

Purpose: The impact of evodiamine in combination with histone deacetylase (HDAC) inhibitors on survival of thyroid carcinoma cells was identified.

Methods: TPC-1 and SW1736 human thyroid carcinoma cells were used.

Results: After treatment with evodiamine and PXD101, cell viability, the percentage of viable cells and Bcl2 protein levels decreased, whereas cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX, acetyl. histone H3 and cleaved PARP, and reactive oxygen species (ROS) production increased. In cells treated with both evodiamine and PXD101, compared with PXD101 alone, decrement of cell viability, the percentage of viable cells, and Bcl2 protein levels as well as increment of cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX and cleaved PARP, and ROS production were significant, causing decrement of Bcl2/Bax ratio. Furthermore, all of the combination index values were <1.0, suggesting synergistic cytotoxicity of two agents. Wortmannin decreased cell viability and the percentage of viable cells, whereas it increased cytotoxic activity and the percentage of apoptotic cells without alteration in ROS production. The changes in cells treated with both evodiamine and suberoylanilide hydroxamic acid or trichostatin A were similar to those in cells treated with both evodiamine and PXD101.

Conclusions: Our results demonstrate that evodiamine synergizes with HDAC inhibitors in inducing cytotoxic activities by involving survival-related proteins and ROS in thyroid carcinoma cells. Moreover, repression of PI3K/Akt signaling synergistically reinforces cytotoxicity of evodiamine combined with HDAC inhibitors in thyroid carcinoma cells.