The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells
| Autor: | Ardeshir Ghavamzadeh, Sepideh Hamzehlou, Javad Tavakkoly-Bazzaz, Davood Bashash, Farzaneh Kordbacheh, Hassan Yousefi, Ahmad Reza Dehpour, Seyedeh H. Mousavi-pak, Fatemeh Esmaeili, Seyyed Mohammad Tavangar, Peiman Haddad, Seyed H. Ghaffari, Majid Momeny, Zivar Alishahi, Sepehr Javadikooshesh, Vasimeh Vahdatirad, Kamran Alimoghaddam |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Survival Apoptosis Models Biological Radiation Tolerance 03 medical and health sciences chemistry.chemical_compound ErbB Receptors 0302 clinical medicine ErbB Cell Movement Cell Line Tumor Survivin medicine Humans Neoplasm Invasiveness Receptor Cell Proliferation Quinazolinones Cell growth General Medicine Dacomitinib Pancreatic Neoplasms 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis FOXM1 Cancer research Molecular Medicine Erlotinib medicine.drug Carcinoma Pancreatic Ductal |
| Zdroj: | Cellular oncology (Dordrecht). 42(4) |
| ISSN: | 2211-3436 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC. |
| Databáze: | OpenAIRE |
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