Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice

Abstract

Metastases rather than primary cancers determine nowadays the survival of patients. One of the most common primary malignancies is colorectal cancer and this type of tumor is characterized by a high tendency to spread metastases to the lung and liver. CD26/DPP4 is a transmembrane molecule with enzymatic functions which cleaves biologically active peptides. Recently, CD26/DPP4 has become the focus of cancer research and it was shown that CD26/DPP4-positive cancer cells display increased metastatic activity. Here, we tested if the CD26/DPP4-inhibitor Vildagliptin suppresses the development and growth of mouse colorectal lung metastases. This inhibitor of CD26/DPP4 was employed on mouse (C57BL/6) colorectal lung metastases, established by intravenous injection of the syngeneic cell line MC38. For mechanistic analysis, a subcutaneous tumor model was used. The treatment with Vildagliptin significantly suppressed both, the incidence and growth of lung metastases. Autophagy markers (LC3, p62, and ATF4) decreased, apoptosis increased (TUNEL, pH3/Ki-76), and the cell cycle regulator pCDC2 was inhibited. In conclusion, we here showed an anti-tumor effect of Vildagliptin via downregulation of autophagy resulting in increased apoptosis and modulation of the cell cycle. We therefore propose Vildagliptin for the evaluation as a new therapeutic approach for the treatment of colorectal cancer lung metastases.

DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness

“…Our results show that DPP4 knockdown cells have lower proliferative activity and enter G0/G1 phase more readily. This finding is in concordance with those observed by Jang et al They showed in their results that after inhibiting DPP4 using vildagliptin, the proliferation of tumor cell was suppressed and the mitotic activity was halted [24]. It is likely that DPP4 regulate the tumor cell growth through generation of chemokines and cytokines, such as IL-6R [7].…”

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

“…DPP‐IV inhibition has also drawn significant attention in the field of cancer treatment or diagnosis because DPP‐IV regulates various biological mechanisms and it has been suggested that it can act either promoting or inhibiting tumor progression depending on cancer cell type and tumor microenvironment . For instance, it has been argued whether DPP‐IV must be or must not be administered to cancer patients with diabetes, whereas other studies support the oral administration of DPP‐IV inhibitors in order to either enhance tumor immunotherapy or to slow the growth of different tumors or to suppress colorectal cancer lung metastases in mice . Other studies have demonstrated their therapeutic effects on obesity, neuropathy, and hepatic and renal pathologies.…”

“…16 For instance, it has been argued whether DPP-IV must be or must not be administered to cancer patients with diabetes, [17][18][19] whereas other studies support the oral administration of DPP-IV inhibitors in order to either enhance tumor immunotherapy 20 or to slow the growth of different tumors 21-23 or to suppress colorectal cancer lung metastases in mice. 24 Other studies have demonstrated their therapeutic effects on obesity, 25-29 neuropathy, 30 and hepatic 31-37 and renal 38-44 pathologies. Recent studies have also shown that it is possible to design DPP-IV inhibitors with dual bioactivity on other targets involved in cardiovascular diseases like ACE 45 or -adrenergic receptors.…”

Quantifying critical states of complex diseases using single-sample dynamic network biomarkers

“…CSF2 is one of the pivotal orchestrators of basal breast cancer growth and metastasis [47]. DPP4 shows positive metastatic activity in cancer cells [48]. FN1 plays a critical role in metastasis and is associated with advanced stages and higher metastatic potential in patients with renal cancer [49–51].…”