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Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells

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Abstract

Purpose

The influence of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the histone deacetylase inhibitor PXD101 on survival of thyroid carcinoma cells was investigated.

Methods

SW1736, TPC-1, 8505C and BCPAP human thyroid carcinoma cells were used. To assess cell survival, cell viability, the percentage of viable cells and dead cells, cytotoxic activity, ATP levels and FACS analysis were measured. To validate the impact of gemigliptin combined with PXD101, the interactions were estimated by obtaining combination index in cells treated with two agents.

Results

In cells treated with gemigliptin or PXD101, cell viability, the percentage of viable cells and ATP levels were reduced, and the percentage of dead cells and cytotoxic activity were elevated. In cells treated with both gemigliptin and PXD101, compared with PXD101 alone, cell death was augmented, and all of the combination index values were lower than 1.0, suggesting the synergism between gemigliptin and PXD101. The percentage of apoptotic cells, and the protein levels of Bcl2 and cleaved poly (ADP-ribose) polymerase were elevated, and the protein levels of xIAP and survivin were reduced. The protein levels of phospho-Akt and phospho-AMPK were elevated, and cell migration was reduced.

Conclusions

Our results demonstrate that gemigliptin induces cytotoxicity in thyroid carcinoma cells. Moreover, gemigliptin has a synergistic activity with PXD101 in the induction of cell death through involvement of Bcl2 family proteins, xIAP and survivin as well as mediation of Akt and AMPK in thyroid carcinoma cells.

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Acknowledgements

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, and also by Hallym University Research Fund 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

    S. H. Kim, J. G. Kang, C. S. Kim, S.-H. Ihm, M. G. Choi, H. J. Yoo & S. J. Lee

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  2. J. G. Kang
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Kim, S.H., Kang, J.G., Kim, C.S. et al. Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. J Endocrinol Invest 41, 677–689 (2018). https://doi.org/10.1007/s40618-017-0792-x

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