The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells

Introduction

Follicular cell–derived thyroid cancer is divided as well-differentiated thyroid carcinoma (WDTC) and undifferentiated thyroid carcinoma (UDTC) according to differentiation of carcinoma cells.¹ WDTC including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) is the most common subtype with an excellent prognosis, but it is refractory to radioactive iodine (RAI) therapy in two thirds of patients with metastatic lesions.¹ UDTC including anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy characterized as extrathyroidal invasion and distant metastasis with a very poor prognosis.^2,3 In clinical situation, the treatment of patients with RAI therapy-refractory WDTC and UDTC is sometimes problematic because of unresponsiveness to conventional therapies, and thus novel therapeutic strategies to improve the outcome of the patients are under consideration.^2,3

Dipeptidyl peptidase-IV (DPP-IV), known as CD26, belongs to serine protease expressed on a variety of cells and cleaves N-terminal depeptides from peptide substrates.^4,5 In human body, DPP-IV rapidly inactivates endogenous incretin such as glucagon-like peptide-1.^4,5 DPP-IV inhibitor stimulates secretion of endogenous incretin, which suppresses blood glucose levels.^4,5 Currently, DPP-IV inhibitor is widely used as monotherapy or combination therapy for treatment of patients with type 2 diabetes mellitus.^4,5

DPP-IV modulates diverse cellular processes including survival, proliferation, and differentiation and thereby enhances or diminishes tumorigenesis relying on types or phases of tumors.⁶ In this regard, DPP-IV is overexpressed or underexpressed in human solid tumor tissues, which is associated with survival, suggesting significance of DPP-IV as a potential diagnostic marker and therapeutic target in solid tumors.⁶ With respect to activity of DPP-IV in thyroid carcinoma cells, it was shown that DPP-IV was seldom active in thyroid follicular cells, whereas it was upregulated in thyroid carcinoma cells.^7–9 Furthermore, it was reported that expression of DPP-IV in aspirated or surgical specimens was abundant in WDTC and absent in follicular adenoma, implying consequence of DPP-IV as a useful tool to aid in distinguishing malignant from benign thyroid tumors.¹⁰ In regard to the influence of DPP-IV inhibitor on cancer, the DPP-IV inhibitors sitagliptin and saxagliptin activate migration and invasion in various cancer cell lines and accelerate development of metastatic nodules in experimental animal models.¹¹ By contrast, it was shown that DPP-IV inhibitor was not related to increased risk...