tacrolimus and Brain-Neoplasms

The heart transplantation is the most important treatment for patients with end-stage severe heart disease who failed to conventional therapy. Post-transplant lymphoproliferative disorder is the second most common malignancy in heart transplant recipients. However, primary central nervous system lymphoma (PCNSL) after heart transplantation is an extremely rare condition.. This report described a 53-year-old male who was diagnosed as PCNSL 17 months after heart transplantation.. The patient was admitted to the local hospital presenting with dizziness, headache, and reduced left-sided power and sensation for 1 week. He had a medical history of heart transplantation because of the dilated cardiomyopathy 17 months ago and had a 17-month history of immunosuppressive therapy with tacrolimus. A computed tomography scan of the brain revealed a bulky mass in the right temporal lobe. The emergency intracranial mass resection and cerebral decompression were performed in our hospital. The histopathology of the brain lesions showed diffuse large B-cell lymphoma. A further FDG positron emission tomography-computed tomography scan of the whole body showed no significantly increased metabolic activity in other regions. The final diagnosis of this patient was PCNSL after heart transplantation.. Given the poor health condition, with the patient's consent, the whole brain radiotherapy was performed with supportive care.. The disease deteriorated rapidly during the period of receiving radiotherapy, and he died within 2 months from the diagnosis.. PCNSL after heart transplantation is an extremely rare phenomenon with extremely poor prognosis. We should pay close attention to the heart recipients, especially when the patients present with neurological symptoms and signs. The available treatment options for PCNS-post-transplant lymphoproliferative disorder include the reduction of immunosuppressive drugs, immune-chemotherapy, operation, radiotherapy. However, individual treatments for heart transplant recipients with PCNSL should be based on the performance status and tolerance to treatment, combined with the doctor's experience and supportive care.

Topics: Brain Neoplasms; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Tacrolimus; Tomography, X-Ray Computed

Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as an MRP1 regulator in differentiated glioblastoma (GBM) cells (non-GSCs); however, the effect of FK506 on GSCs is currently unknown. The objective of the following research is to evaluate the effect of FK506 on the MRP1-related chemo-resistant phenotype of GSCs. For this, U87MG and C6 glioma cell lines were used to generate non-GSCs and GSCs. mRNA and MRP1-positive cells were evaluated by RT-qPCR and flow cytometry, respectively. A Carboxyfluorescein Diacetate (CFDA)-retention assay was performed to evaluate the MRP1 activity. Apoptosis and MTT assays were employed to evaluate the cytotoxic effects of FK506 plus Vincristine (MRP1 substrate). GSC-derived subcutaneous tumors were generated to evaluate the in vivo effect of FK506/Vincristine treatment. No differences in transcript levels and positive cells for MRP1 were observed in FK506-treated cells. Lesser cell viability, increased apoptosis, and CFDA-retention in the FK506/Vincristine-treated cells were observed. In vivo, the FK506/Vincristine treatment decreased the tumor size as well as ki67, Glial Fibrillary Acidic Protein (GFAP), and nestin expression. We conclude that FK506 confers a chemo-sensitive phenotype to MRP1-drug substrate in GSCs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Humans; Male; Multidrug Resistance-Associated Proteins; Neoplastic Stem Cells; Phenotype; Rats, Sprague-Dawley; Tacrolimus; Vincristine

Tacrolimus is a widely used macrolide immunosuppressant in transplant surgery, with mild and major neurologic side effects. A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother. On the 1st postoperative day, the patient had headache, nausea, vomiting, and agitation. Magnetic resonance imaging (MRI) of the brain showed hyperintensity and a lesion in the right mesial temporal lobe. After we switched from tacrolimus to cyclosporine, the symptoms regressed. Persistence of the lesion, confirmed by repeated MRI, required that the patient be operated on. Pathologic examination showed the gangliocytoma, a rare brain tumor. Our case shows that preexisting brain lesions may cause tacrolimus-induced neurotoxicity in the early postoperative period.

Topics: Brain Neoplasms; Cyclosporine; Female; Ganglioneuroma; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Neurotoxicity Syndromes; Tacrolimus; Transplant Recipients; Young Adult

Members of the nuclear factor of activated T cells (NFAT) family have been identified as regulators of oncogenic transformation in several human malignancies. A prominent member of this family, NFAT1, is associated with tumor cell survival, apoptosis, migration and invasion. Here, we investigated the role of NFAT1 in glioma cells. In 111 clinical samples, microarray analysis demonstrated that NFAT1 was over-expressed in glioblastoma multiforme (GBM), compared with low-grade gliomas, a result confirmed by RT-PCR in 24 clinical samples and in the U87 and U251 cell lines. Immunohistochemistry and immunofluorescence stain indicated that over-expressed NFAT1 was mainly located in the nucleus, where it acted as a transcription factor. After treatment with the NFAT antagonist cyclosporin A (CsA) and FK506, levels of NFAT1 in the nuclei of U87 GBM cells were dramatically reduced. The invasive potential of U87 cells was reduced by the same treatment, as well as by inhibition of NFAT1 expression using small hairpin RNA. Proliferation of U87 cells was unaffected by CsA, FK506 and NFAT1 shRNA transfection. Clustering analysis and Pearson correlation analysis of microarray data showed that the expression of NFAT1 correlated with the expression of the invasion-related genes cyclooxygenase-2 (COX-2), matrix metalloproteinase-7 (MMP-7) and MMP-9, a result confirmed by in vitro analysis. These findings demonstrate that NFAT1 contributes to the invasive potential but not the proliferation of GBM cells, and suggest that CsA may find application as an adjuvant in combined treatment strategies for GBM.

Topics: Biopsy; Brain Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cyclooxygenase 2; Cyclosporine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NFATC Transcription Factors; Oligonucleotide Array Sequence Analysis; RNA, Small Interfering; Tacrolimus

Glioblastoma multiforme (GBM) is the most aggressive of brain tumors and is extremely insensitive to anticancer drugs. Studies have attributed the ABC transporter Mrp1 (ABCC1, multiple-drug resistance protein 1) with conferring chemoresistance in this tumor by extrusion of a wide spectrum of anticancer drugs. Therefore it is crucial to search for and investigate inhibitors of Mrp1 activity in GBM cells, particularly those that could be safe as chemosensitizers to anticancer drugs in clinical studies. We find that in primary cultured or T98G GBM cells exposed to therapeutic plasma concentrations of FK506 (tacrolimus), the expression of Mrp1 was decreased in a dose-dependent manner. The activity of this transporter, measured by CFDA fluorescent substrate extrusion, decreased significantly in primary cultured GBM cells on exposure to FK506 at concentrations of 15 ng/ml. When GBM cells were exposed to anticancer drugs vincristine, etoposide or taxol, cell viability was not affected. However when the anticancer drugs were assayed in combination with FK506, cell viability was significantly decreased by as much as 50% in GBM primary culture. We conclude that FK506 could be a valuable tool for chemosensitization of GBM cells, offering a possible improvement to the current poor therapy available for high-grade human gliomas.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Humans; Immunosuppressive Agents; Multidrug Resistance-Associated Proteins; Tacrolimus

Topics: Antilymphocyte Serum; Brain Neoplasms; Cytomegalovirus Retinitis; Epstein-Barr Virus Infections; Female; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisolone; Radiography; RNA, Viral; Tacrolimus; Transplantation, Homologous

To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H20O)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pre-treatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the anti-apoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.

Topics: Apoptosis; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Cell Survival; Glial Cell Line-Derived Neurotrophic Factor; Glioma; Glutathione; Humans; Hydrogen Peroxide; Immunophilins; Ligands; Nerve Growth Factors; Pyridines; Pyrrolidines; Tacrolimus

Topics: Animals; Antibodies, Monoclonal; Blotting, Western; Brain Chemistry; Brain Neoplasms; Carrier Proteins; Cerebellum; Cerebral Cortex; DNA-Binding Proteins; Heat-Shock Proteins; Hippocampus; Humans; Neuroblastoma; Olfactory Bulb; Organ Specificity; Rats; Recombinant Proteins; Tacrolimus; Tacrolimus Binding Proteins; Tumor Cells, Cultured