sitagliptin-phosphate and Carcinoma--Renal-Cell

Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4

Topics: Aged; Aged, 80 and over; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance, Neoplasm; Female; Humans; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Protein Kinase Inhibitors; Sitagliptin Phosphate; Spheroids, Cellular; Sunitinib; Survival Rate; Xenograft Model Antitumor Assays

The aim of this study was to assess the effect of sitagliptin with or without resveratrol on carcinogen-induced clear cell renal cell carcinoma. Sixty male Wistar rats were divided into 6 equal groups as follows: control; clear cell renal cell carcinoma group; clear cell renal cell carcinoma+sitagliptin group; clear cell renal cell carcinoma+resveratrol group; clear cell renal cell carcinoma+carboxymethyl cellulose group and clear cell renal cell carcinoma+sitagliptin+resveratrol group. Blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-d-glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT) and urinary albumin excretion rate (UAER) were determined. Renal tissue antioxidant enzymes, lactate dehydrogenase (LDH), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducers and activators of transcription-3 (STAT3) were determined. Parts of the kidneys were subjected to histopathological and immunohistochemical examination for nuclear factor kappa B (p65). Sitagliptin and/or resveratrol induced significant improvement of the renal functions with significant increase in tissue antioxidant defenses and Nrf2/HO-1 content associated with significant decrease in tissue LDH, TGF-β1, TNF-α, IL-6 and STAT3 and alleviated the histopathological and immunohistochemical changes compared to the untreated clear cell renal cell carcinoma group. These effects were significant in sitagliptin/resveratrol combination group compared to the use of each of these drugs alone. In conclusion, sitagliptin/resveratrol combination might represent a beneficial therapeutic modality for amelioration of experimentally-induced clear cell renal cell carcinoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Carcinoma, Renal Cell; Immunohistochemistry; Kidney Function Tests; Kidney Neoplasms; Male; Neoplasms, Experimental; Rats; Rats, Wistar; Resveratrol; Sitagliptin Phosphate; Stilbenes