Novel heat shock protein 90 inhibitor NVP-AUY922 synergizes with the histone deacetylase inhibitor PXD101 in induction of death of anaplastic thyroid carcinoma cells.

Abstract

The influence of the novel heat shock protein 90 (hsp90) inhibitor NVP-AUY922 (AUY922) on anaplastic thyroid carcinoma (ATC) cells has not been investigated. The effect of AUY922 alone or in combination with the histone deacetylase inhibitor PXD101 on survival of ATC cells was evaluated. In ATC cells, AUY922, compared with 17-allylamino-17-demethoxygeldanamycin, herbimycin A and radicicol, potently lead to growth inhibition and cell death with cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) and concomitant changes in expression of hsp90 client proteins. After treatment of both AUY922 and PXD101, compared with treatment of AUY922 or PXD101 alone, the percentage of nonviable cells, annexin V-stained cells, and cytotoxic activity increased. All of the combination index values were lower than 1.0, suggesting the synergism between AUY922 and PXD101 in induction of cell death. In cells treated with both AUY922 and PXD101, compared with cells treated with AUY922 alone, the protein levels of phospho-Akt, cellular inhibitor of apoptosis protein, X-linked inhibitor of apoptosis protein, survivin, ataxia telangiectasia mutated (ATM), and ATM and Rad-3 related (ATR) decreased, whereas those of acetyl. histone H3, acetyl. histone H4, phospho-histone H2A.X, cleaved DFF45, and cleaved PARP increased. Our results demonstrate that AUY922 potently induces cytotoxicity with concomitant modulation of hsp90 client proteins in ATC cells. Moreover, AUY922 has a synergistic activity with PXD101 in induction of cytotoxicity in conjunction with the inactivation of PI3K/Akt signaling and survivin and the activation of DNA damage response in ATC cells.