Characterisation of a novel matrix metalloproteinase inhibitor on pancreatic adenocarcinoma cells in vitro and in an orthotopic pancreatic cancer model in vivo

Abstract

Matrix metalloproteinases (MMPs) play a central role in tissue maintenance, inflammation and during tumour invasion and metastasis. The impact of MMPs in cancer has encouraged the development of novel MMP-inhibitors without adverse effects on the cell viability. We describe here the synthesis and characterisation of a triazinederivative as a highly potent MMP-inhibitor. The new compound Triazin 17-2 was developed on the basis of a triazine backbone as a well known and well tolerated chemical scaffold. It was de novo synthesized and tested for MMP inhibition in a cell free assay. In vitro characterisation included tests for cell viability, protein expression and MMP activity in PancTu-1 cells. Effectivity of MMP inhibition was analysed in vitro by invasion assay. Triazin 17-2 was investigated in vivo using an orthotopic pancreatic ductal adenocarcinoma (PDAC) xenograft model in SCID/bg mice. Triazin 17-2 proved to have no adverse effects on cell viability in vitro at concentrations effectively inhibiting MMPs in an invasion assay. Application of Triazin 17-2 in vivo in the orthotopic PDAC model in SCID/bg mice showed a significant reduction of primary tumour weight using conservative therapy and inhibition of metastasis in adjuvant therapy. The MMP-inhibitor Triazin 17-2 was developed and characterised in vitro and in vivo. The new compound has no intrinsic activity to kill cells but is very effective in inhibition of MMPs. In vivo testing revealed that MMP-inhibitors are useful tools in anticancer therapy reducing tumour size and invasion even without direct effects on cell survival.