The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells

The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and...

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Bibliographic Details
Published in:Endocrine 2016-02, Vol.51 (2), p.274-282
Main Authors: Kim, Si Hyoung, Kang, Jun Goo, Kim, Chul Sik, Ihm, Sung-Hee, Choi, Moon Gi, Yoo, Hyung Joon, Lee, Seong Jin
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Benzamides - pharmacology
Benzamides - therapeutic use
Caspase 3 - metabolism
Cell Line, Tumor
Cell Survival - drug effects
Diabetes
Drug Synergism
Endocrinology
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylase Inhibitors - therapeutic use
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Humanities and Social Sciences
Humans
Hydroxamic Acids - pharmacology
Hydroxamic Acids - therapeutic use
Indazoles - pharmacology
Indazoles - therapeutic use
Internal Medicine
Medicine
Medicine & Public Health
multidisciplinary
Original Article
Phosphorylation - drug effects
Proto-Oncogene Proteins c-akt - metabolism
Science
Thyroid Carcinoma, Anaplastic - drug therapy
Thyroid Carcinoma, Anaplastic - metabolism
Thyroid Carcinoma, Anaplastic - pathology
Thyroid Neoplasms - drug therapy
Thyroid Neoplasms - metabolism
Thyroid Neoplasms - pathology
Vorinostat
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Summary:The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells.
ISSN:1355-008X
1559-0100
DOI:10.1007/s12020-015-0706-7