sitagliptin-phosphate and Breast-Neoplasms

To date, the main clinical interest in DPP4 is focused on its inhibition in diabetic patients to prolong the half-life of incretins. Epigenetic alterations resulting from DPP4 inhibition have been poorly explored.. The objective of this study was to determine, whether sitagliptin, a DPP4 inhibitor, has effects on the expression of KAT7 and SIRT1 (genes encoding a histone acetyltransferase and a histone deacetylase, respectively) in MCF7 breast cancer cells, which play an essential role in modulating the epigenetic landscape of chromatin.. MCF7 cells were incubated for 20 h with sitagliptin at concentrations of 0.5, 1.0 and 2.0 μM. Total RNA was isolated and the relative mRNA expression of KAT7 and SIRT1 was determined by RT-qPCR.. There was downregulation in the relative expression of both genes; for KAT7, downregulation reached up to 0.49 (p = 0.027) and for SIRT1, it reached up to 0.55 (p = 0.037).. These results suggest that sitagliptin has effects on the histone epigenetic landscape. This topic deserves further study due to the current sample use of DPP4 inhibitors in diabetic patients.. Hasta la fecha, el principal interés clínico de la DPP4 se centra en su inhibición en pacientes diabéticos para prolongar la vida media de las incretinas. Las alteraciones epigenéticas resultantes de la inhibición de DPP4 han sido poco exploradas.. Determinar si la sitagliptina, un inhibidor de DPP4, tiene efectos sobre la expresión de KAT7 y SIRT1 (genes que codifican una histona acetiltransferasa y una histona desacetilasa, respectivamente) en células de cáncer de mama MCF7, que desempeñan un papel esencial en la modulación del paisaje epigenético de la cromatina.. Las células MCF7 se incubaron durante 20 h con sitagliptina a concentraciones de 0.5, 1.0 y 2.0 μM. Se aisló el ARN total y se determinó la expresión relativa de ARNm de KAT7 y SIRT1 mediante RT-qPCR.. Hubo una regulación a la baja en la expresión relativa de ambos genes; para KAT7, la regulación negativa alcanzó hasta 0.49 (p = 0.027) y para SIRT1 alcanzó hasta 0.55 (p = 0.037).. Estos resultados sugieren que la sitagliptina tiene efectos sobre el paisaje epigenético de las histonas. Este tema merece más estudios debido al uso actual de inhibidores de DPP4 en pacientes diabéticos.

Topics: Breast Neoplasms; Dipeptidyl Peptidase 4; Down-Regulation; Female; Gene Expression; Histone Acetyltransferases; Humans; MCF-7 Cells; Sirtuin 1; Sitagliptin Phosphate

Whether sitagliptin may affect breast cancer risk remains to be answered. This study evaluated such an association in Taiwanese female patients with type 2 diabetes.. A retrospective cohort of female patients with newly diagnosed type 2 diabetes at an age ≥ 25 years between 1999 and 2010 was recruited from the National Health Insurance database. A total of 32,457 ever-users and 396,021 never-users of sitagliptin were followed until December 31, 2011. The treatment effect was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Sensitivity analyses were conducted in a matched cohort.. During follow-up, 78 ever-users and 2204 never-users were diagnosed with breast cancer, representing an incidence of 150.44 and 215.87 per 100,000 person-years, respectively. The hazard ratio (95% confidence intervals [CIs]) for ever- versus never-users was 0.718 (95% CI, 0.573-0.901). The hazard ratio for the first, second, and third tertile of cumulative duration < 5.73, 5.73-12.73, and > 12.73 months was 0.783 (95% CI, 0.523-1.171), 1.021 (95% CI, 0.723-1.441), and 0.455 (95% CI, 0.296-0.700), respectively; and was 0.823 (95% CI, 0.554-1.222), 0.918 (95% CI, 0.639-1.317), and 0.499 (95% CI, 0.331-0.753) for cumulative dose < 14,400, 14,400-33,800, and > 33,800 mg, respectively. Findings were supported by analyses in the matched cohort.. Sitagliptin may reduce breast cancer risk in female patients with type 2 diabetes mellitus, especially 1 year after its use.

Topics: Adult; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Taiwan

Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis.. Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1), and the cytotoxic effects of combined treatment with sitagliptin and juglone were investigated by immunohistochemistry, immunoblotting, real-time PCR, TUNEL and soft agar assays, using MCF7 cells. The effects of sitagliptin on tumour development in vivo were studied in the syngeneic 4T1 metastatic breast cancer model.. Activity of the transcription factor E2F1 induced by EGF was enhanced by DPP4, thus increasing PIN1 expression. Furthermore, DPP4 enhanced MEK/ERK and JNK/c-Jun signalling induced by EGF, inducing AP-1 activity and epithelial cell transformation. In contrast, DPP4 silencing or DPP4 inhibition in MCF7 cells inhibited PIN1 expression via E2F1 activity induced by EGF, decreasing colony formation and inducing DNA fragmentation. In the syngeneic 4T1 metastatic breast cancer model, DPP4 overexpression increased tumour development, whereas treatment with sitagliptin and/or juglone suppressed it. Consistent with these observations, DPP4 levels were positively correlated with PIN1 expression in human breast cancer.. DPP4 promoted EGF-induced epithelial cell transformation and mammary tumourigenesis via induction of PIN1 expression, suggesting that sitagliptin targeting of DPP4 could be a treatment strategy in patients with breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Transformation, Neoplastic; Cyclin D1; Dipeptidyl Peptidase 4; Epidermal Growth Factor; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Protein Kinases; Signal Transduction; Sitagliptin Phosphate; Transcription Factor AP-1; Up-Regulation

Topics: Animals; Breast Neoplasms; Calcitonin; Carcinoma, Medullary; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infections; Liraglutide; Pancreatitis; Pharmacovigilance; Pioglitazone; Pyrazines; Risk Assessment; Safety-Based Drug Withdrawals; Sitagliptin Phosphate; Species Specificity; Thiazolidinediones; Thyroid Neoplasms; Triazoles; Urinary Bladder Neoplasms