Table 4.

Summary of studies evaluating direct cytotoxic effects of gliptins.

Tumor Type	Gliptin	Effective Gliptin Concentrations in In Vitro Studies	References, Notes
Colorectal cancer	Vildagliptin	Cytotoxicity: 2–10 mM for single exposure and >0.328 mM for repeated exposure. Reduced expression of EMT markers: 10–20 µM Reduced cyclin-dependent kinase 1 phosphorylation: 0.08–0.16 mM	Suppression of lung metastases also observed in an animal model [64].
	Sitagliptin	Cytotoxicity: above 0.5 mM, lower concentrations did not substantially influence cell growth. Inhibition of motility and invasion: 0.5 mM	[142]
Thyroid cancer	Gemigliptin	Cytotoxicity: 0.5–2 mM Effect in other assays (reduced migration, induction of apoptosis etc.): 0.25–1 mM. At this concentration, some cytotoxicity was seen in normal bronchial epithelial cells.	Synergistic cytotoxic effects with a histone deacetylase inhibitor, metformin, and a Hsp90 inhibitor [138,139,140].
	Sitagliptin, vildagliptin	Reduced cell growth: 1 mM Decreased migration and invasion: 10–100 nM	Decreased tumor growth was also observed in a xenotransplantation mouse model [60].
Gastric cancer	Sitagliptin	Inhibition of growth and colony formation: 1–2 mM Inhibition of YAP signaling: 1–2 mM	[141]
Breast cancer	Sitagliptin	Decreased cell viability and activation of apoptotic signaling: 0.5–2.5 mM Decreased colony formation: 0.1–1 mM Inhibition of EGF signaling: 0.5–1 mM	Cells pretreated with sitagliptin (10 mM) form smaller tumors in experimental animals [78].
Endometrial cancer	Sitagliptin	Decreased cell growth: 2–8 mM Decreased migration: 1 mM	[82]
Hepatocellular carcinoma	Sitagliptin	No effect on cell growth or synergy with doxurubicine derivative WP 631 toxicity: 0.01–200 µM	[143]
Cervical carcinoma	Sitagliptin	Compromised cellular integrity (LDH release): >2 mM Decreased viability: >0.2 mM Decreased cell adhesion 1 mM	Effects are independent of DPP-IV expression [144].
Acute myeloid leukemia	Vildagliptin	10 µM vildagliptin but not 10 µM sitagliptin enhances the cytotoxic effect of parthenolide.	Effects caused by DPP8 and DPP9 inhibition [145].
Multiple myeloma	Vildagliptin, saxagliptin	Cytotoxicity: 0.005–0.1 mM	Effects caused by DPP9 inhibition [146].
Chronic myeloid leukemia	Vildagliptin, sitagliptin, saxagliptin	No effect on cell growth or synergy with tyrosinkinase inhibitors: 10 nM–10 µM Reduced mobilization of leukemic stem cells from a stroma cell layer: 5–10 µM	Gliptins enhance SDF-1 induced migration, but do not affect colony formation. Preincubation with vildagliptin decreased engraftment of leukemic cells in mice. Gliptin treatment led to decreased BCR/ABL1 transcript levels in two patients [147]. Effect on engraftment was not confirmed in a follow-up study [148].