Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 2/2018

01-02-2018 | Original Article

Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells

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

Published in: Endocrine | Issue 2/2018

Login to get access

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, phospho-Akt 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 molecule-1 (VCAM-1), and phospho-extracellular signal-regulated kinase (ERK) 1/2 decreased. The decrement of matrix 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.
Appendix
Available only for authorised users
Literature
1.
S. Bulotta, M. Celano, G. Costante, D. Russo, Emerging strategies for managing differentiated thyroid cancers refractory to radioiodine. Endocrine 52, 214–221 (2016)CrossRefPubMed
2.
3.
E.E. Mulvihill, D.J. Drucker, Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 35, 992–1019 (2014)CrossRefPubMed
4.
5.
P.A. Havre, M. Abe, Y. Urasaki, K. Ohnuma, C. Morimoto, N.H. Dang, The role of CD26/dipeptidyl peptidase IV in cancer. Front. Biosci. 13, 1634–1645 (2008)CrossRefPubMed
6.
A. Kehlen, U. Lendeckel, H. Dralle, J. Langner, C. Hoang-Vu, Biological significance of aminopeptidase N/CD13 in thyroid carcinomas. Cancer Res. 63, 8500–8506 (2003)PubMed
7.
O. Fluge, O. Bruland, L.A. Akslen, J.R. Lillehaug, J.E. Varhaug, Gene expression in poorly differentiated papillary thyroid carcinomas. Thyroid 16, 161–175 (2006)CrossRefPubMed
8.
T. Kotani, Y. Aratake, Y. Ogata, K. Umeki, Y. Araki, K. Hirai, K. Kuma, S. Ohtaki, Expression of dipeptidyl aminopeptidase IV activity in thyroid carcinoma. Cancer Lett. 57, 203–208 (1991)CrossRefPubMed
9.
W. Rathmann, K. Kostev, Association of dipeptidyl peptidase 4 inhibitors with risk of metastases in patients with type 2 diabetes and breast, prostate or digestive system cancer. J. Diabetes Complicat. 31, 687–692 (2017)CrossRefPubMed
10.
H. Wang, X. Liu, M. Long, Y. Huang, L. Zhang, R. Zhang, Y. Zheng, X. Liao, Y. Wang, Q. Liao, W. Li, Z. Tang, Q. Tong, X. Wang, F. Fang, M.R. de la Vega, Q. Ouyang, D.D. Zhang, S. Yu, H. Zheng, NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci. Transl. Med. 8, 334ra51 (2016)CrossRefPubMed
11.
S.H. Kim, S.H. Lee, H.J. Yim, Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry. Arch. Pharm. Res. 36, 1185–1188 (2013)CrossRefPubMed
12.
S.H. Kim, E. Jung, M.K. Yoon, O.H. Kwon, D.M. Hwang, D.W. Kim, J. Kim, S.M. Lee, H.J. Yim, Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo. Eur. J. Pharmacol. 788, 54–64 (2016)CrossRefPubMed
13.
H.J. Hwang, H.S. Chung, T.W. Jung, J.Y. Ryu, H.C. Hong, J.A. Seo, S.G. Kim, N.H. Kim, K.M. Choi, D.S. Choi, S.H. Baik, H.J. Yoo, The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms. Mol. Cell. Endocrinol. 405, 25–34 (2015)CrossRefPubMed
14.
H.J. Hwang, T.W. Jung, J.Y. Ryu, H.C. Hong, H.Y. Choi, J.A. Seo, S.G. Kim, N.H. Kim, K.M. Choi, D.S. Choi, S.H. Baik, H.J. Yoo, Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes. Mol. Cell. Endocrinol. 392, 1–7 (2014)CrossRefPubMed
15.
J.Y. Moon, J.S. Woo, J.W. Seo, A. Lee, D.J. Kim, Y.G. Kim, S.Y. Kim, K.H. Lee, S.J. Lim, X.W. Cheng, S.H. Lee, W. Kim, The dose-dependent organ-specific effects of a dipeptidyl peptidase-4 inhibitor on cardiovascular complications in a model of type 2 diabetes. PLoS. ONE 11, e0150745 (2016)CrossRefPubMedPubMedCentral
16.
G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J. Ventre, T. Doebber, N. Fujii, N. Musi, M.F. Hirshman, L.J. Goodyear, D.E. Moller, Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001)CrossRefPubMedPubMedCentral
17.
G.W. Landman, N. Kleefstra, K.J. van Hateren, K.H. Groenier, R.O. Gans, H.J. Bilo, Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33, 322–326 (2010)CrossRefPubMed
18.
J. Klubo-Gwiezdzinska, J. Costello Jr., A. Patel, A. Bauer, K. Jensen, M. Mete, K.D. Burman, L. Wartofsky, V. Vasko, Treatment with metformin is associated with higher remission rate in diabetic patients with thyroid cancer. J. Clin. Endocrinol. Metab. 98, 3269–3279 (2013)CrossRefPubMed
19.
J. Klubo-Gwiezdzinska, K. Jensen, J. Costello, A. Patel, V. Hoperia, A. Bauer, K.D. Burman, L. Wartofsky, V. Vasko, Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr. Relat. Cancer 19, 447–456 (2012)CrossRefPubMed
20.
B. Han, H. Cui, L. Kang, X. Zhang, Z. Jin, L. Lu, Z. Fan, Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol. 36, 6295–6304 (2015)CrossRef
21.
S.W. Cho, K.H. Yi, S.K. Han, H.J. Sun, Y.A. Kim, B.C. Oh, Y.J. Park, D.J. Park, Therapeutic potential of metformin in papillary thyroid cancer in vitro and in vivo. Mol. Cell. Endocrinol. 393, 24–29 (2014)CrossRefPubMed
22.
G. Chen, S. Xu, K. Renko, M. Derwahl, Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J. Clin. Endocrinol. Metab. 97, E510–E520 (2012)CrossRefPubMed
23.
S. Lim, K.A. Han, J. Yu, P. Chamnan, E.S. Kim, K.H. Yoon, S. Kwon, M.K. Moon, K.W. Lee, D.J. Kim, M. Kim, M. Wongtanate, E.Y. Kim, S.H. Kim, M.K. Lee, Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: a double-blind randomized controlled trial (INICOM study). Diabetes Obes. Metab. 19, 87–89 (2017)CrossRefPubMed
24.
B. Omar, B. Ahren, Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors. Diabetes 63, 2196–2202 (2014)CrossRefPubMed
25.
K. Kato, J. Gong, H. Iwama, A. Kitanaka, J. Tani, H. Miyoshi, K. Nomura, S. Mimura, M. Kobayashi, Y. Aritomo, H. Kobara, H. Mori, T. Himoto, K. Okano, Y. Suzuki, K. Murao, T. Masaki, The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol. Cancer Ther. 11, 549–560 (2012)CrossRefPubMed
26.
M.A. Lea, J. Pourat, R. Patel, C. desBordes Growth inhibition of colon cancer cells by compounds affecting AMPK activity.World J. Gastrointest. Oncol. 6, 244–252 (2014)CrossRefPubMedPubMedCentral
27.
R. Rattan, S. Giri, L.C. Hartmann, V. Shridhar, Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J. Cell. Mol. Med. 15, 166–178 (2011)CrossRefPubMed
28.
A. Frid, G.N. Sterner, M. Löndahl, C. Wiklander, A. Cato, E. Vinge, A. Andersson, Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 33, 1291–1293 (2010)CrossRefPubMedPubMedCentral
29.
I. Ben Sahra, K. Laurent, A. Loubat, S. Giorgetti-Peraldi, P. Colosetti, P. Auberger, J.F. Tanti, Y. Le Marchand-Brustel, F. Bost, The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27, 3576–3586 (2008)CrossRefPubMed
30.
S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Inhibition of p21 and Akt potentiates SU6656-induced caspase-independent cell death in FRO anaplastic thyroid carcinoma cells. Horm. Metab. Res. 45, 408–414 (2013)CrossRefPubMed
31.
S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Suppression of AKT potentiates synergistic cytotoxicity of apigenin with TRAIL in anaplastic thyroid carcinoma cells. Anticancer. Res. 35, 6529–6537 (2015)PubMed
32.
S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Akt inhibition enhances the cytotoxic effect of apigenin in combination with PLX4032 in anaplastic thyroid carcinoma cells harboring BRAFV600E. J. Endocrinol. Invest. 36, 1099–1104 (2013)PubMed
33.
H.-J. Choi, T.Y. Kim, N. Chung, J.H. Yim, W.G. Kim, J. Kim, W.B. Kim, Y.K. Shong, The influence of the BRAFV600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside. J. Endocrinol. 211, 79–85 (2011)CrossRefPubMed
34.
M.W. Roomi, J.C.Monterrey, T. Kalinovsky, M.Rath, A.Niedzwiecki, Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. Oncol. Rep. 21, 1323–1333 (2009).PubMed
35.
N. Esfahanian, Y. Shakiba, B. Nikbin, H. Soraya, N. Maleki-Dizaji, M. Ghazi-Khansari, A. Garjani, Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells. Mol. Med. Rep. 5, 1068–1074 (2012).CrossRefPubMedPubMedCentral
36.
P. Li, M. Zhao, A.B. Parris, X. Feng, X. Yang, p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochem. Biophys. Res. Comm. 464, 1267–1274 (2015)CrossRefPubMed
37.
F. Vittone, A. Liberman, D. Vasic, R. Ostertag, M. Esser, D. Walcher, A. Ludwig, N. Marx, M. Burgmaier, Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe−/− mice. Diabetologia 55, 2267–2275 (2012)CrossRefPubMed
38.
W. Guo, F.G. Giancotti, Integrin signalling during tumour progression. Nat. Rev. Mol. Cell. Biol. 5, 816–826 (2004)CrossRefPubMed
39.
M. Schlesinger, G. Bendas, Vascular cell adhesion molecule-1(VCAM-1)-an increasing insight into its role in tumorigenicity and metastasis. Int. J. Cancer 136, 2504–2514 (2015)CrossRefPubMed
40.
Y. Zeng, C. Li, M. Guan, Z. Zheng, J. Li, W. Xu, L. Wang, F. He, Y. Xue, The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms. Cardiovasc. Diabetol. 13, 32 (2014)CrossRefPubMedPubMedCentral
41.
C. Wang, L. Qin, T.D. Manes, N.C. Kirkiles-Smith, G. Tellides, J.S. Pober, Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2. J. Exp. Med. 211, 395–404 (2014)CrossRefPubMedPubMedCentral
42.
Z.N. Zhuang, Z.J. Xu, Q. Zhou, X.Z. Xu, J. Tian, Y.F. Liu, S. Guo, J.Y. Wang, K.S. Xu, Clinical significance of integrin β6 as a tumor recurrence factor in follicular thyroid carcinoma. Head. Neck 37, 1439–1447 (2015)CrossRefPubMed
43.
Z. Pasieka, K. Kuzdak, W. Czyz, H. Stępień, J. Komorowski, Soluble intracellular adhesion molecules (sICAM-1, sVCAM-1) in peripheral blood of patients with thyroid cancer. Neoplasma 51, 34–37 (2004)PubMed
44.
T.P. Kobawala, T.I. Trivedi, K.K. Gajjar, D.H. Patel, G.H. Patel, N.R. Ghosh, Significance of TNF-α and the adhesion molecules: L-selectin and VCAM-1 in papillary thyroid carcinoma. J. Thyroid. Res. 2016, 8143695 (2016)PubMedPubMedCentral
Metadata
Title
Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells
Authors
Si Hyoung Kim
Jun Goo Kang
Chul Sik Kim
Sung-Hee Ihm
Moon Gi Choi
Hyung Joon Yoo
Seong Jin Lee
Publication date
01-02-2018
Publisher
Springer US
Published in
Endocrine / Issue 2/2018
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-017-1503-2

Other articles of this Issue 2/2018

Endocrine 2/2018 Go to the issue

Original Article

Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors

Original Article

The tear cytokine profile in patients with active Graves’ orbitopathy

Review

Raising awareness on the therapeutic role of cholecalciferol in CKD: a multidisciplinary-based opinion

Original Article

Effects of growth hormone on thyroid function are mediated by type 2 iodothyronine deiodinase in humans

Clinical Management of Endocrine Diseases

Prevalence of morphometric vertebral fractures in “difficult” patients with acromegaly with different biochemical outcomes after multimodal treatment

Letter to the Editor

Long lasting prophylaxis of iodine deficiency after a successful information campaign for iodized salt consumption
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits