-
Biomedicine & Pharmacotherapy =... Sep 2022The complex of formononetin and calycosin (FMN/CAL) shows a synergistic effect on temozolomide in the treatment of malignant glioma, however the mechanism is unclear. We...
The complex of formononetin and calycosin (FMN/CAL) shows a synergistic effect on temozolomide in the treatment of malignant glioma, however the mechanism is unclear. We investigated the mechanism through means of metabolomics, network pharmacology and molecular biology. FMN/CAL enhanced the inhibition of TMZ on the growth and infiltration of C6 glioma. The metabolomic results showed that the TMZ sensitization of FMN/CAL mainly involved 5 metabolic pathways and 4 metabolites in cells, 1 metabolic pathway and 2 metabolites in tumor tissues, and 7 metabolic pathways and 8 metabolites in serum. Further network pharmacological analysis revealed that NOS2 was a potential target for FMN/CAL to regulate the metabolism in TMZ-treated C6 glioma cells, serums and tissues, and TNF-α was another potential target identified in tissues. FMN/CAL down-regulated the expression of NOS2 in tumor cells and tissues, and reduced the secretion of TNF-α in tumor region. FMN/CAL promoted TMZ-induced C6 cell apoptosis by inhibiting NOS2, but the inhibition of cell vitality and migration was not through NOS2. Our work revealed that FMN/CAL can increase the sensitivity of malignant glioma to TMZ by inhibiting NOS2-dependent cell survival, which provides a basis for the application of this combination in adjuvant treatment of glioma.
Topics: Humans; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioma; Isoflavones; Network Pharmacology; Temozolomide; Tumor Necrosis Factor-alpha
PubMed: 36076540
DOI: 10.1016/j.biopha.2022.113418 -
Cancer Jul 2007Malignant gliomas are relatively uncommon but lethal cancers. Despite recent research efforts in cancer therapy, the prognosis of patients with malignant gliomas has... (Review)
Review
Malignant gliomas are relatively uncommon but lethal cancers. Despite recent research efforts in cancer therapy, the prognosis of patients with malignant gliomas has remained dismal. Understanding the molecular pathogenesis of glioma may lead to a rational development of new therapies. Despite the genetic heterogeneity of malignant gliomas, common aberrations in the signaling elements of the growth and survival pathways are found. New treatments have emerged to target molecules in these signaling pathways with the goal to increase specific efficacy and minimize toxicity. Monoclonal antibodies and low molecular-weight kinase inhibitors are the most common classes of agents in targeted cancer treatment. Most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit in unselected malignant glioma patient populations. Several mechanisms of treatment failure have been demonstrated. In response, multitargeted kinase inhibitors and combinations of single-targeted kinase inhibitors have been developed to overcome therapeutic resistance. In addition, multimodality combinations of targeted agents with radiation, chemotherapy, or immunotherapy/vaccines may enhance treatment efficacy. Future development of these agents will require advances in discovery and validation of new molecular targets, improvement of therapeutic delivery, and identification of correlative biomarkers. Novel clinical trial designs and endpoints may increase the efficiency of new drug evaluation. In this review, the authors discussed the current understanding of molecular pathogenesis and the development of molecularly targeted therapies in malignant glioma.
Topics: Brain Neoplasms; Combined Modality Therapy; Glioma; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Receptors, Growth Factor; Signal Transduction
PubMed: 17520692
DOI: 10.1002/cncr.22741 -
Molecular Medicine (Cambridge, Mass.) Jan 2021Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers...
BACKGROUND
Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma.
METHODS
Bioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy.
RESULTS
Bioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling.
CONCLUSION
Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Glioma; Humans; Mice; Mitochondrial Membrane Transport Proteins; Neoplasm Invasiveness; Oxidative Phosphorylation; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 33509092
DOI: 10.1186/s10020-020-00261-4 -
Current Neurology and Neuroscience... Jul 2010Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful,... (Review)
Review
Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential.
Topics: Brain Neoplasms; Clinical Trials as Topic; Glioma; Immunotherapy; Treatment Outcome
PubMed: 20424975
DOI: 10.1007/s11910-010-0111-9 -
Neoplasia (New York, N.Y.) Apr 2017Human glioma, in particular, malignant forms such as glioblastoma exhibit dismal survival rates despite advances in treatment strategies. A population of glioma cells... (Review)
Review
Human glioma, in particular, malignant forms such as glioblastoma exhibit dismal survival rates despite advances in treatment strategies. A population of glioma cells with stem-like features, glioma cancer stem-like cells (GCSCs), contribute to renewal and maintenance of the tumor cell population and appear responsible for chemotherapeutic and radiation resistance. Bone morphogenetic protein 4 (BMP4), drives differentiation of GCSCs and thus improves therapeutic efficacy. Based on this observation it is imperative that the clinical merits of BMP4 in treating human gliomas should be addressed. This article reviews BMP4 signaling in central nervous system development and in glioma tumorigenesis, and the potential of this molecule as a treatment target in human gliomas. Further work needs to be done to determine if distinct lineages of GCSCs, associated with different glioma sub-classifications, proneural, neural, classical and mesenchymal, differ in responsiveness to BMP4 treatment. Additionally, interaction among BMP4 and cell matrix, tumor-vascular molecules and microglial immune cells also needs to be investigated, as this will enhance our knowledge about the role of BMP4 in human glioma and lead to the identification and/or development of novel therapeutic approaches that improve treatment outcomes of these devastating tumors.
Topics: Bone Morphogenetic Protein 4; Brain Neoplasms; Carrier Proteins; Cell Transformation, Neoplastic; Central Nervous System; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Humans; Phenotype; Protein Binding; Radiation Tolerance; Signal Transduction; Tumor Microenvironment
PubMed: 28278424
DOI: 10.1016/j.neo.2017.01.006 -
Neuro-oncology Jun 2018A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current... (Review)
Review
A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current therapeutics. Connexin 43 (Cx43), a gap junction protein, plays important roles not only in the development of the central nervous system and but also in the progression of glioma. The different structural domains of Cx43, including extracellular loops, transmembrane domains, and an intracellular carboxyl terminal, have distinct functions in the invasion and proliferation of gliomas. Targeting these domains of Cx43, which is expressed in distinct patterns in the heterogeneous glioma cell population, can inhibit tumor cell invasion and new tumor formation. Thus, this review summarizes the structural characteristics of Cx43, the effects of regulating different Cx43 domains on the biological characteristics of glioma cells, intervention strategies targeting different domains of Cx43, and future research directions.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Connexins; Glioma; Humans; Molecular Targeted Therapy; Prognosis; Protein Domains
PubMed: 29106645
DOI: 10.1093/neuonc/nox207 -
Neuro-oncology Jan 2017Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are...
BACKGROUND
Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.
METHODS
We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.
RESULTS
We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.
CONCLUSIONS
Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Epoxy Compounds; Fatty Acids; Glioma; Glycolysis; Humans; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Neural Stem Cells; Oxidation-Reduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 27365097
DOI: 10.1093/neuonc/now128 -
Oncology Reports Dec 2017BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma,...
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable for 27 months, 7 months and 3 months, respectively. One patient showed a dramatic radiologic and clinical response after one week of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib resulted in reduced cell density and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
Topics: Adult; Cell Line, Tumor; Glioma; Humans; Imidazoles; MAP Kinase Signaling System; Male; Meningeal Neoplasms; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oximes; Phosphorylation; Proto-Oncogene Proteins B-raf
PubMed: 29039591
DOI: 10.3892/or.2017.6013 -
International Journal of Nanomedicine 2021Glioma is the most common and malignant primary brain tumour in adults and has a dismal prognosis. Temozolomide (TMZ) is the only clinical first-line chemotherapy drug...
Accurately Controlled Delivery of Temozolomide by Biocompatible UiO-66-NH Through Ultrasound to Enhance the Antitumor Efficacy and Attenuate the Toxicity for Treatment of Malignant Glioma.
BACKGROUND
Glioma is the most common and malignant primary brain tumour in adults and has a dismal prognosis. Temozolomide (TMZ) is the only clinical first-line chemotherapy drug for malignant glioma up to present. Due to poor aqueous solubility and toxic effects, TMZ is still inefficient and limited for clinical glioma treatment.
METHODS
UiO-66-NH nanoparticle is a zirconium-based framework, constructed by Zr and 2-amino-1,4-benzenedicarboxylic acid (BDC-NH) with octahedral microporous structure, which can be decomposed by the body into an ionic form to discharge. We prepared the nanoscale metal-organic framework (MOF) of UiO-66-NH to load TMZ for therapy of malignant glioma, TMZ is released from UiO-66-NH through a porous structure. The ultrasound accelerates its porous percolation and promotes the rapid dissolution of TMZ through low-frequency oscillations and cavitation effect. The biological safety and antitumor efficacy were evaluated both in vitro and in vivo.
RESULTS
The prepared TMZ@MOF exhibited excellent biocompatibility and biosafety due to minimal drug leakage without ultrasound intervention. We further used the flank model of glioblastoma to verify the in vivo therapeutic effect. TMZ@UiO-66-NH nanocomposites could be well delivered to the tumour tissue, which led to local enrichment of the TMZ concentration. Furthermore, TMZ@UiO-66-NH nanocomposites under ultrasound demonstrated much more efficient inhibition for tumor growth than TMZ@UiO-66-NH nanocomposites and TMZ alone. Meanwhile, the bone marrow suppression side effects of TMZ were significantly reduced by TMZ@UiO-66-NH nanocomposites.
CONCLUSION
In this work, TMZ@UiO-66-NH nanocomposites with ultrasound mediation could effectively improve the killing effect of malignant glioma and decrease TMZ-induced toxicity in normal tissues, demonstrating great potential for the delivery of TMZ in the clinical treatment of malignant gliomas.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Glioma; Humans; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 34675514
DOI: 10.2147/IJN.S330187 -
Scientific Reports Sep 2017Malignant glioma is the most common brain cancer with dismal outcomes. Individual variation of the patients' survival times is remarkable. Here, we investigated the...
Malignant glioma is the most common brain cancer with dismal outcomes. Individual variation of the patients' survival times is remarkable. Here, we investigated the transcriptome and promoter methylation differences between patients of malignant glioma with short (less than one year) and the patients with long (more than three years) survival in CGGA (Chinese Glioma Genome Atlas), and validated the differences in TCGA (The Cancer Genome Atlas) to identify the genes whose expression levels showed high concordance with prognosis of glioma patients, as well as played an important role in malignant progression. The gene coding a key enzyme in genetic material synthesis, dCMP deaminase (DCTD), was found to be significantly correlated with overall survival and high level of DCTD mRNA indicated shorter survival of the patients with malignant glioma in different databases. Our finding revealed DCTD as an efficient prognostic factor for malignant glioma. As DCTD inhibitor gemcitabine has been proposed as an adjuvant therapy for malignant glioma, our finding also suggests a therapeutic value of gemcitabine for the patients with high expression level of DCTD.
Topics: Adolescent; Adult; Aged; Computational Biology; DCMP Deaminase; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Ontology; Genomics; Glioma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Neoplasm Grading; Prognosis; RNA, Messenger; Transcriptome; Young Adult
PubMed: 28912488
DOI: 10.1038/s41598-017-11962-y