erucylphospho-n-n-n-trimethylpropylammonium and Glioblastoma

Integrin-dependent adhesion of tumor cells to extracellular matrix proteins provides anchorage-dependent protection from cell death. In the present investigation we aimed to understand whether and how the paradigmatic membrane-targeted synthetic phospholipid analog erufosine is relevant for tumor cell adhesion to extracellular matrix proteins, cell survival and migration. The antineoplastic action of erufosine was analyzed with glioblastoma and prostate cancer cells adhering to fibronectin or collagen I using proliferation, adhesion and migration assays. The composition of adhesion contacts containing activated β1 integrins was studied using immunofluorescence. The importance of β1 integrins for the observed effects was analyzed in fibroblasts proficient or deficient in β1 integrin expression. Adhesion to collagen I and fibronectin increased the death threshold in serum-deprived tumor cells. Moreover, β1 integrin-deficient cells were more sensitive to erufosine-treatment compared to β1 integrin proficient cells suggesting a role of β1 integrins for matrix-mediated death resistance. Most importantly, erufosine disturbed the maturation of the cell adhesion complexes containing paxillin, activated β1 integrins and phosphorylated FAK, leading to a reduction of survival signals and inhibition of tumor cell adhesion and migration. These findings suggest that membrane-targeted synthetic phospholipids analogs may be of value for counteracting matrix-mediated treatment resistance in combined treatment approaches with radiotherapy or chemotherapy.

Topics: Animals; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Survival; Collagen Type I; Extracellular Matrix; Fibroblasts; Fibronectins; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Glioblastoma; Humans; Integrin beta1; Male; Mice; Organophosphates; Paxillin; Phosphorylation; Prostatic Neoplasms; Quaternary Ammonium Compounds

On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis-resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using (18)F-DPA-714 PET.. In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with (18)F-DPA-714 for the time of treatment.. A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in (18)F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic protein-positive astrocytes.. Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using (18)F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain; Brain Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Fluorine Radioisotopes; Gene Expression Regulation, Neoplastic; Glioblastoma; Male; Organophosphates; Positron-Emission Tomography; Pyrazoles; Pyrimidines; Quaternary Ammonium Compounds; Rats; Receptors, GABA-A; Treatment Outcome

Erufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro.. In the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice.. We show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed.. We conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Chemoradiotherapy; Glioblastoma; Humans; Mice; Mice, Nude; Organophosphates; Quaternary Ammonium Compounds; Radiotherapy; Tissue Distribution; Xenograft Model Antitumor Assays