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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.
Highlights
Photodynamic therapy (PDT) is built on the selective accumulation of a photosensitizer (PS) in cancer cells followed by photoinduced generation of highly cytotoxic singlet oxygen and other reactive oxygen species [1], which induce oxidative stress leading to necrotic or apoptotic cell death
Our results showed that photofrin based PDT followed by miR-99a overexpression could directly or indirectly inhibit fibroblast growth factor receptor 3 (FGFR3) and PI3K/Akt signaling mechanisms to trigger the p53-mediated caspase-dependent pathway of apoptosis in the p53 wild-type glioblastoma cells both in vitro and in vivo
After determining optimum incubation times for photofrin, all six glioblastoma cell lines were subjected to photofrin based PDT with light doses ranging from 0 to 2.5 J/cm2 with 0.5 J/cm2 increment
Summary
Photodynamic therapy (PDT) is built on the selective accumulation of a photosensitizer (PS) in cancer cells followed by photoinduced generation of highly cytotoxic singlet oxygen and other reactive oxygen species [1], which induce oxidative stress leading to necrotic or apoptotic cell death. PDT provides a new tactic for an effective treatment of the hard-to-treat tumors like glioblastoma. Glioblastoma is the most common and most aggressive type of primary brain tumor in humans. The median survival time of glioblastoma patients is 14.6 months [2]. One of the important characteristic features of glioblastoma cells is their diffuse infiltrative nature [3]. It has been observed that fluorescence-guided resection and repetitive PDT can significantly prolong median survival in glioblastoma patients [4,5]. Despite these promising observations, various issues have to be addressed to optimize PDT as a useful therapeutic option for glioblastoma patients
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