Therapeutic effects of Argyrin F in pancreatic adenocarcinoma

• Published in: Cancer letters Vol. 399; pp. 20 - 28
• Main Authors: Chen, Xi, Bui, Khac Cuong, Barat, Samarpita, Thi Nguyen, Mai Ly, Bozko, Przemyslaw, Sipos, Bence, Kalesse, Markus, Malek, Nisar P, Plentz, Ruben R
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.07.2017; Elsevier Limited
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Argyrin F; Cancer therapies; Carcinoma, Pancreatic Ductal - blood supply; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - secondary; Cell cycle; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Experiments; G1 Phase Cell Cycle Checkpoints - drug effects; Hematology, Oncology and Palliative Medicine; Histology; Humans; Medical prognosis; Metastasis; Mice, Transgenic; Neoplasm Invasiveness; Neovascularization, Pathologic; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PDAC; Peptides, Cyclic - pharmacology; Proteasomes; Protein Stability; Rodents; Signal Transduction - drug effects; Survival analysis; Therapeutic efficacy; Time Factors; Tumor Burden - drug effects; Tumors; Wound healing; United States > US; Germany; Argyrin F; Therapeutic efficacy; Chemotherapy; PDAC
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.04.003

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options. The proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra , shows antitumoral activities. We hypothesize that his analogue Argyrin F (AF) may also prevent PDAC progression. We have used PDAC cells and engineered mice (Pdx1-Cre; LSL-KrasG12D; p53lox/+ ) to assess AF anticancer activity. We analyzed the effect of AF on proliferation and epithelial plasticity using MTT-, wound healing-, invasion-, colony formation-, apoptosis-, cell cycle- and senescence assays. In vivo treatment with AF, Gemcitabine (G) and combinational treatment (AF+G) was performed for survival analysis. AF inhibited cell proliferation, migration, invasion and colony formation in vitro . AF impaired epithelial-mesenchymal-transition (EMT), caused considerable apoptosis and senescence in a dose- and time-dependent manner and affected cell cycle G1 /S phase transition. G treatment achieved longest mice survival, followed by AF+G and AF compared to vehicle group. However, AF+G treatment induced the largest reduction in tumor spread and ascites. In conclusion, we have demonstrated that AF prevents PDAC progression and that combined therapy was superior to AF monotherapy. Therefore, AF treatment might be useful as an additional therapy for PDAC.