title: 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.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
authors.forename: Lesley
authors.initials: L
authors.lastname: Baerts
authors.affiliation: Department of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Waumans
authors.affiliation: Department of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Visceral and Transplantation Surgery, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gil-Bazo
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland. wolfgang.jungraithmayr@usz.ch.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009570:Nitriles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D000077597:Vildagliptin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000077597:Vildagliptin; D000218:Adamantane
keywords: Apoptosis; Autophagy; CD26/DPP4; Lung metastases