title: Biodegradable interstitial release polymer loading a novel small molecule targeting Axl receptor tyrosine kinase and reducing brain tumour migration and invasion.
abstract: Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour. The neoplasms are difficult to resect entirely because of their highly infiltration property and leading to the tumour edge is unclear. Gliadel wafer has been used as an intracerebral drug delivery system to eliminate the residual tumour. However, because of its local low concentration and short diffusion distance, patient survival improves non-significantly. Axl is an essential regulator in cancer metastasis and patient survival. In this study, we developed a controlled-release polyanhydride polymer loading a novel small molecule, n-butylidenephthalide (BP), which is not only increasing local drug concentration and extending its diffusion distance but also reducing tumour invasion, mediated by reducing Axl expression. First, we determined that BP inhibited the expression of Axl in a dose- and time-dependent manner and reduced the migratory and invasive capabilities of GBM cells. In addition, BP downregulated matrix metalloproteinase activity, which is involved in cancer cell invasion. Furthermore, we demonstrated that BP regulated Axl via the extracellular signal-regulated kinases pathway. Epithelial-to-mesenchymal transition (EMT) is related to epithelial cells in the invasive migratory mesenchymal cells that underlie cancer progression; we demonstrated that BP reduced the expression of EMT-related genes. Furthermore, we used the overexpression of Axl in GBM cells to prove that Axl is a crucial target in the inhibition of GBM EMT, migration and invasion. In an in vivo study, we demonstrated that BP inhibited tumour growth and suppressed Axl expression in a dose-dependent manner according to a subcutaneous tumour model. Most importantly, in an intracranial tumour model with BP wafer in situ treatment, we demonstrated that the BP wafer not only significantly increased the survival rate but also decreased Axl expression, and inhibited tumour invasion. These results contribute to the development of a BP wafer for a novel therapeutic strategy for treating GBM invasion and increasing survival in clinical subjects.
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Yen
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: S-R
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Molecular Medicine Program, National Taiwan University, Taipei, Taiwan.
authors.forename: J
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Li
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: S-E
authors.initials: SE
authors.lastname: Chuang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: H-M
authors.initials: HM
authors.lastname: Chuang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: M-H
authors.initials: MH
authors.lastname: Huang
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan.|Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan.|Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan.
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Department of Pathology, China Medical University Hospital, Taichung, Taiwan.|Department of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Harn
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: T-W
authors.initials: TW
authors.lastname: Chiou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016503:Drug Delivery Systems; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010796:Phthalic Anhydrides / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D010796:Phthalic Anhydrides; D011108:Polymers; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; C026105:butylidenephthalide; D000094963:Axl Receptor Tyrosine Kinase