Characterisation of a novel matrix metalloproteinase inhibitor on pancreatic adenocarcinoma cells in vitro and in an orthotopic pancreatic cancer model in vivo.
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 triazine-derivative 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.
Kapischke
Matthias
M
Department of Surgery, Martin Luther Hospital, D-24837 Schleswig, Germany. mkapischke@web.de
Fischer
Tim
T
Tiessen
Katrin
K
Tschesche
Harald
H
Bruch
Hans-Peter
HP
Kalthoff
Holger
H
Kruse
Marie-Luise
ML
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013450:Sulfones; D014227:Triazines; C527367:triazin 17-2