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: Jae-Hwi Jang, Lesley Baerts, Yannick Waumans, Ingrid De Meester, Yoshito Yamada, Perparim Limani, Ignacio Gil-Bazo, Walter Weder, Wolfgang Jungraithmayr
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 32 Issue 7 Pg. 677-87 (Oct 2015) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 26233333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Nitriles
• Pyrrolidines
• Dipeptidyl Peptidase 4
• Dpp4 protein, mouse
• Vildagliptin
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (pathology)
• Dipeptidyl Peptidase 4 (metabolism)
• Humans
• In Situ Nick-End Labeling
• Lung Neoplasms (secondary)
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (drug therapy)
• Nitriles (pharmacology)
• Pyrrolidines (pharmacology)
• Vildagliptin
• Xenograft Model Antitumor Assays