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

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Abstract

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.

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Abbreviations

17-AAG:

17-allylamino-17-demethoxygeldanamycin

ATC:

Anaplastic thyroid carcinoma

CI:

Combination index

cIAP:

Cellular inhibitor of apoptosis protein

DMSO:

Dimethylsulfoxide

ED50 :

The concentrations of each drug required for 50 % inhibition

FTC:

Follicular thyroid carcinoma

HDAC:

Histone deacetylase

Hsp70:

Heat shock protein 70

Hsp90:

Heat shock protein 90

IAP:

Inhibitor of apoptosis protein

PARP:

Poly(ADP-ribose) polymerase

PTC:

Papillary thyroid carcinoma

γH2AX:

Phospho-histone H2A.X

SAHA:

Suberoylanilide hydroxamic acid

TSA:

Trichostatin A

xIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) (No. 2015R1A2A2A01003589) to S.J. Lee, Republic of Korea.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea

    Si Hyoung Kim, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo & Seong Jin Lee

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  1. Si Hyoung Kim
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Kim, S.H., Kang, J.G., Kim, C.S. et al. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells. Endocrine 51, 274–282 (2016). https://doi.org/10.1007/s12020-015-0706-7

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