minocycline and Brain-Neoplasms

Glioblastoma multiforme (GBM) is the most prevalent and aggressive form of glioma, with poor prognosis and high mortality rates. As GBM is a highly vascularized cancer, antiangiogenic therapies to halt or minimize the rate of tumor growth are critical to improving treatment. In this review, antiangiogenic therapies, including small-molecule drugs, nucleic acids and proteins and peptides, are discussed. The authors further explore biomaterials that have been utilized to increase the bioavailability and bioactivity of antiangiogenic factors for better antitumor responses in GBM. Finally, the authors summarize the current status of biomaterial-based targeting moieties that target endothelial cells in GBM to more efficiently deliver therapeutics to these cells and avoid off-target cell or organ side effects.

Topics: Angiogenesis Inhibitors; Biocompatible Materials; Brain Neoplasms; Combined Modality Therapy; Docetaxel; Glioblastoma; Humans; Minocycline; Nucleic Acids; Small Molecule Libraries

There are no effective treatments for gliomas after progression on radiation, temozolomide, and bevacizumab. Microglia activation may be involved in radiation resistance and can be inhibited by the brain penetrating antibiotic minocycline. In this phase 1 trial, we examined the safety and effect on survival, symptom burden, and neurocognitive function of reirradiation, minocycline, and bevacizumab.. The trial used a 3 + 3 design for dose escalation followed by a ten person dose expansion. Patients received reirradiation with dosing based on radiation oncologist judgment, bevacizumab 10 mg/kg IV every two weeks, and oral minocycline twice a day. Symptom burden was measured using MDASI-BT. Neurocognitive function was measured using the COGSTATE battery.. The maximum tolerated dose of minocycline was 400 mg twice a day with no unexpected toxicities. The PFS3 was 64.6%, and median overall survival was 6.4 months. Symptom burden and neurocognitive function did not decline in the interval between treatment completion and tumor progression.. Minocycline 400 mg orally twice a day with bevacizumab and reirradiation is well tolerated by physician and patient reported outcomes in people with gliomas that progress on bevacizumab.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Chemoradiotherapy; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Glioma; Humans; Male; Middle Aged; Minocycline; Neoplasm Grading; Prospective Studies; Retreatment; Survival Rate

Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, is effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. Studying mechanisms underlying the therapeutic effects of CpG-C, we found that in the brain, unlike in the periphery, natural killer (NK) cells and monocytes are not involved in controlling metastasis. Next, we demonstrated that the systemically administered CpG-C is taken up by endothelial cells, astrocytes, and microglia, without affecting blood-brain barrier (BBB) integrity and tumor brain extravasation. In vitro assays pointed to microglia, but not astrocytes, as mediators of CpG- C effects through increased tumor killing and phagocytosis, mediated by direct microglia-tumor contact. In vivo, CpG-C-activated microglia displayed elevated mRNA expression levels of apoptosis-inducing and phagocytosis-related genes. Intravital imaging showed that CpG-C-activated microglia cells contact, kill, and phagocytize tumor cells in the early stages of tumor brain invasion more than nonactivated microglia. Blocking in vivo activation of microglia with minocycline, and depletion of microglia with a colony-stimulating factor 1 inhibitor, indicated that microglia mediate the antitumor effects of CpG-C. Overall, the results suggest prophylactic CpG-C treatment as a new intervention against brain metastasis, through an essential activation of microglia.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Colony-Stimulating Factors; Female; Humans; Lung Neoplasms; Male; Melanoma; Mice; Microglia; Minocycline; Oligodeoxyribonucleotides; Phagocytosis; Signal Transduction; Toll-Like Receptor 9

Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported.. Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures.. We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity.. Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Auranofin; Brain Neoplasms; Captopril; Celecoxib; Disulfiram; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Glioblastoma; Humans; Itraconazole; Mice; Mice, SCID; Minocycline; Neoplastic Stem Cells; Quetiapine Fumarate; Reproducibility of Results; Sertraline; Signal Transduction; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133. GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo.. CD133. The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma.

Topics: AC133 Antigen; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Proliferation; Drug Combinations; Drug Synergism; Glioblastoma; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Minocycline; Neoplastic Stem Cells; Rats; STAT3 Transcription Factor; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Over the past several years, there has been increasing interest in combining angiogenesis inhibitors with radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma. Although the US FDA approved bevacizumab for the treatment of glioblastoma in 2009, the European Medicines Agency rejected its use due to its questionable impact on patient survival. One factor contributing to the failure of angiogenesis inhibitors to increase overall patient survival may be their inability to cross the blood-brain barrier. Here the authors examined in a 9L glioma model whether intracranial polymer-based delivery of the angiogenesis inhibitor minocycline potentiates the effects of both radiotherapy and temozolomide chemotherapy in increasing median survival. The authors also investigated whether the relative timing of minocycline polymer implantation with respect to radiotherapy affects the efficacy of radiotherapy.. Minocycline was incorporated into the biodegradable polymer polyanhydride poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]) (CPP:SA) at a ratio of 50:50 by weight. Female Fischer 344 rats were implanted with 9L glioma on Day 0. The minocycline polymer was then implanted on either Day 3 or Day 5 posttumor implantation. Cohorts of rats were exposed to 20 Gy focal radiation on Day 5 or were administered oral temozolomide (50 mg/kg daily) on Days 5-9.. Both minocycline polymer implantations on Days 3 and 5 increased survival from 14 days to 19 days (p < 0.001 vs control). Treatment with a combination of both minocycline polymer and radiotherapy on Day 5 resulted in a 139% increase in median survival compared with treatment with radiotherapy alone (p < 0.005). There was not a statistically significant difference in median survival between the group that received minocycline implanted on the same day as radiotherapy and the group that received minocycline polymer 2 days prior to radiotherapy. Lastly, treatment with a combination of minocycline polymer with oral temozolomide resulted in a 38% extension of median survival compared with treatment of oral temozolomide alone (p < 0.001).. These results show that minocycline delivered locally potentiates the effects of both radiotherapy and oral temozolomide in increasing median survival in a rodent glioma model. More generally, these results suggest that traditional therapy in combination with local, as opposed to systemic, delivery of angiogenesis inhibitors may be able to increase median survival for patients with glioblastoma.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemoradiotherapy; Combined Modality Therapy; Dacarbazine; Disease Models, Animal; Drug Delivery Systems; Female; Gliosarcoma; Minocycline; Neoplasm Transplantation; Polymers; Rats; Rats, Inbred F344; Temozolomide

The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease (MMP) 2, MMP9 and membrane-type 1 MMP. In this work we demonstrate that, MMP9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of MMP9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signaling pathway for the glioma induced upregulation of microglial MMP9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial MMP9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of MMP9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen-activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy.

Topics: Animals; Anti-Bacterial Agents; Blotting, Western; Brain Neoplasms; Disease Models, Animal; Flow Cytometry; Fluorescent Antibody Technique; Glioma; Humans; Immunoenzyme Techniques; Macrophages; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Toll-Like Receptor 2; Tumor Cells, Cultured

We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic.. Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice.. The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP.. Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Brain Neoplasms; Cell Line; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Glioma; Heat-Shock Proteins; Humans; Mice; Microtubule-Associated Proteins; Minocycline; Rats; Signal Transduction; Transcription Factor CHOP

Minocycline, a tetracycline family antibiotic, is known to inhibit microglial activation and proinflammatory cytokine release in animal models. Experimental data show that these immune processes may play a role in epilepto- and ictogenesis. We present the case of a patient with marked reduction in seizure frequency during minocycline therapy with severe symptomatic epilepsy due to an astrocytoma.

Topics: Anticonvulsants; Astrocytoma; Brain Neoplasms; Epilepsy; Humans; Male; Melanoma; Middle Aged; Minocycline; Neoplasms, Multiple Primary; Skin Neoplasms

Glioma cells release soluble factors, which induce the expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and then exploit MT1-MMP mediated matrix degradation for invasion. Here, we show that minocycline blocked the increase in MT1-MMP expression and activity in cultivated microglia stimulated with glioma conditioned medium. Glioma growth within an organotypic brain slice preparation was reduced by minocycline and this reduction depended on the presence of microglia. Glioma growth in an experimental mouse model was strongly reduced by the addition of minocycline to drinking water, compared to untreated controls. Coherently, we observed in our orthotopic glioma implantation model, that MT1-MMP was abundantly expressed in glioma associated microglia in controls, but was strongly attenuated in tumors of minocycline treated animals. Overall, our study indicates that the clinically approved antibiotic minocycline is a promising new candidate for adjuvant therapy against malignant gliomas.

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Cells, Cultured; Chemotherapy, Adjuvant; Culture Media, Conditioned; Glioma; Matrix Metalloproteinase 14; Mice; Microglia; Minocycline; Neoplasm Invasiveness; Neoplasms, Experimental; Organ Culture Techniques

Minocycline is neuroprotective in animal models of a number of acute CNS injuries, neurodegenerative diseases and CNS infection. While anti-inflammatory and anti-apoptotic effects of Minocycline have been characterized, the molecular basis for the neuroprotective effects of Minocycline remains unclear. We report here that Minocycline and two classical antioxidant compounds inhibit the Japanese Encephalitis Virus (JEV)-induced free radical generation in mouse neuroblastoma. In cultures of Neuro2a (N2a) cells infected with JEV for up to 24h, the number of cells undergoing cell death was also reduced by Minocycline (20 microM). JEV infection resulted in increased oxidative stress, as revealed by an increase in the fluorescence intensity for 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA), a reactive oxygen species (ROS) indicator. Minocycline at 20 microM inhibited this ROS production. Cells were moderately protected from JEV-induced death by diphenyleneiodonium (DPI), an inhibitor of flavon-containing enzyme inhibitor, whereas common antioxidants such as N-acetyl-cysteine (NAC) turned out to be ineffective. Direct antioxidant property of Minocycline and reference antioxidant compounds is evaluated by LDH assay, ROS measurement and mitochondrial membrane potential measurement. Our findings suggest that Minocycline reduces the neuronal damage seen in JEV infection in neuronal cell culture models at least in part through inhibition of oxidative stress.

Topics: Acetylcysteine; Animals; Anisotropy; Anti-Bacterial Agents; Antioxidants; Blotting, Western; Brain Neoplasms; Cell Death; Cell Line, Tumor; Encephalitis, Japanese; Enzyme Inhibitors; Free Radicals; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Membrane Fluidity; Membrane Potentials; Mice; Mice, Inbred BALB C; Minocycline; Mitochondrial Membranes; Neuroblastoma; Onium Compounds; Reactive Oxygen Species

Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.

Topics: Absorbable Implants; Animals; Anti-Bacterial Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Delayed-Action Preparations; Drug Evaluation, Preclinical; Drug Synergism; Female; Gliosarcoma; Minocycline; Neoplasm Transplantation; Rats; Rats, Inbred F344; Treatment Outcome

This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Combined Modality Therapy; Delayed-Action Preparations; Gliosarcoma; Male; Minocycline; Neoplasm Transplantation; Rats; Rats, Inbred F344

A 16-year-old girl developed headaches and bilateral papilledema while taking minocycline for acne. The initial neuro-ophthalmologic evaluation was normal except for enlarged blind spots OU. An MRI scan demonstrated subtle abnormalities. A lumbar puncture was entirely normal except for an increased opening pressure. A tentative diagnosis of pseudotumor cerebri was made and the patient was treated with Diamox. A second MRI was unchanged, and a lumbar puncture performed while the patient was taking Diamox was entirely normal. The patient subsequently lost vision in both eyes, and a third MRI now revealed a supracellar enhancing mass. Biopsy and subtotal resection of the mass showed it to be a glioblastoma multiforme. This case emphasizes pitfalls in the diagnosis of pseudotumor cerebri. Careful follow-up and a high index of suspicion in pseudotumor cerebri syndromes are essential.

Topics: Adolescent; Brain Neoplasms; Diagnosis, Differential; Female; Fundus Oculi; Glial Fibrillary Acidic Protein; Glioblastoma; Humans; Magnetic Resonance Imaging; Minocycline; Papilledema; Pseudotumor Cerebri; Visual Fields