title: Photofrin based photodynamic therapy and miR-99a transfection inhibited FGFR3 and PI3K/Akt signaling mechanisms to control growth of human glioblastoma In vitro and in vivo.
abstract: Glioblastoma is the most common malignant brain tumor in humans. We explored the molecular mechanisms how the efficacy of photofrin based photodynamic therapy (PDT) was enhanced by miR-99a transfection in human glioblastoma cells. Our results showed almost similar uptake of photofrin after 24 h in different glioblastoma cells, but p53 wild-type cells were more sensitive to radiation and photofrin doses than p53 mutant cells. Photofrin based PDT induced apoptosis, inhibited cell invasion, prevented angiogenic network formation, and promoted DNA fragmentation and laddering in U87MG and U118MG cells harvoring p53 wild-type. Western blotting showed that photofrin based PDT was efficient to block the angiogenesis and cell survival pathways. Further, photofrin based PDT followed by miR-99a transfection dramatically increased miR-99a expression and also increased apoptosis in glioblastoma cell cultures and drastically reduced tumor growth in athymic nude mice, due to down regulation of fibroblast growth factor receptor 3 (FGFR3) and PI3K/Akt signaling mechanisms leading to inhibition of cell proliferation and induction of molecular mechanisms of apoptosis. Therefore, our results indicated that the anti-tumor effects of photofrin based PDT was strongly augmented by miR-99a overexpression and this novel combination therapeutic strategy could be used for controlling growth of human p53 wild-type glioblastomas both in vitro and in vivo.
authors: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
authors: Mrinmay
authors: M
authors: Chakrabarti
authors: Naren L
authors: NL
authors: Banik
authors: Swapan K
authors: SK
authors: Ray
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020552:Comet Assay; D017323:Dihematoporphyrin Ether / Q000494:pharmacology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D035683:MicroRNAs / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010778:Photochemotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D017323:Dihematoporphyrin Ether; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051498:Receptor, Fibroblast Growth Factor, Type 3; C561679:MIRN99 microRNA, human; C496365:FGFR3 protein, human