Novel heat shock protein 90 inhibitor NVP-AUY922 synergizes with the histone deacetylase inhibitor PXD101 in induction of death of anaplastic thyroid carcinoma cells.
BACKGROUND
The influence of the novel heat shock protein 90 (hsp90) inhibitor NVP-AUY922 (AUY922) on anaplastic thyroid carcinoma (ATC) cells has not been investigated.


OBJECTIVE
The effect of AUY922 alone or in combination with the histone deacetylase inhibitor PXD101 on survival of ATC cells was evaluated.


RESULTS
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.


CONCLUSIONS
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.
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Si Hyoung
SH
Kim
Jun Goo
JG
Kang
Chul Sik
CS
Kim
Sung-Hee
SH
Ihm
Moon Gi
MG
Choi
Hyung Joon
HJ
Yoo
Seong Jin
SJ
Lee
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007555:Isoxazoles; D012118:Resorcinols; D013449:Sulfonamides; C487081:belinostat