Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells
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ORIGINAL ARTICLE
Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells Si Hyoung Kim1 Jun Goo Kang1 Chul Sik Kim1 Sung-Hee Ihm1 Moon Gi Choi1 Hyung Joon Yoo1 Seong Jin Lee1 ●
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Received: 22 August 2017 / Accepted: 12 December 2017 © Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract Purpose The influence of the dipeptidyl peptidase-IV inhibitor, gemigliptin alone or in combination with metformin on survival, proliferation, and migration of thyroid carcinoma cells was investigated. Methods SW1736 and TPC-1 human thyroid carcinoma cells were used. Results Gemigliptin and metformin caused cell death in a dose-dependent manner. In cells treated with both gemigliptin and metformin, compared with metformin alone, all of the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of two agents. Cell viability, the percentage of viable cells, ATP levels, and mitochondrial membrane potential decreased; however, cytotoxic activity, and the protein levels of cleaved PARP, phosphoAkt and phospho-AMP-activated protein kinase (AMPK) increased. Administration of wortmannin, but not compound C, further decreased cell viability, and further increased cytotoxic activity. Moreover, compared with control, cell proliferation and migration as well as the protein levels of p53, p21, vascular cell adhesion molecule1 (VCAM-1), and phospho-extracellular signal-regulated kinase (ERK) 1/2 decreased. The decrement of matrix
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12020-017-1503-2) contains supplementary material, which is available to authorized users. * Seong Jin Lee [email protected] 1
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
metalloproteinase-2 and matrix metalloproteinase-9 protein levels was cell specific. Conclusions Our results demonstrate that gemigliptin induces cytotoxic activity, and has a synergistic activity with metformin in inducing cytotoxicity via regulation of Akt and AMPK in thyroid carcinoma cells. Furthermore, gemigliptin augments the inhibitory effect of metformin on proliferation and migration through involvement of matrix metalloproteinase-2, matrix metalloproteinase-9, p53, p21, VCAM-1, and ERK in thyroid carcinoma cells. Keywords Thyroid carcinoma Dipeptidyl peptidase-IV Gemigliptin Metformin Synergism ●
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Abbreviations AMPK AMP-activated protein kinase ATC Anaplastic thyroid carcinoma CI Combination index DMSO Dimethylsulfoxide DPP-IV Dipeptidyl peptidase-IV ED50 The concentrations of each drug required for 50% inhibition ERK Extracellular signal-regulated kinase MMP-2 Matrix metalloproteinase-2 MMP-9 Matrix metalloproteinase-9 PARP Poly (ADP-ribose) polymerase PTC Papillary thyroid carcinoma VCAM-1 Vascular cell adhesion molecule-1
Introduction Although well-differentiated thyroid carcinoma (WDTC) including papillary th
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