RESUMEN
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
Asunto(s)
Neoplasias Encefálicas , Diabetes Mellitus Tipo 2 , Glioblastoma , Metformina , Animales , Metformina/farmacología , Metformina/uso terapéutico , Glioblastoma/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Proliferación Celular , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular TumoralRESUMEN
Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , AutofagiaRESUMEN
Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamiento farmacológico , GMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Microambiente TumoralRESUMEN
In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Apoptosis , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Humanos , Óxido Nítrico , Transducción de SeñalRESUMEN
Glioblastoma multiforme (GBM) continues as one of the most lethal cerebral cancers despite standard therapeutic modalities, such as maximum surgical resection and chemoradiation. The minimal effectiveness of existing therapies necessitates the development of additional drug candidates that could improve the prognosis of GBM patients. Accumulating evidence suggests that calcium (Ca2+) is involved in the processes of cell proliferation, metastasis, angiogenesis, migration, and invasiveness. Therefore, Ca2+ could serve as a crucial regulator of tumorigenesis and a potential treatment target in GBM. In this context, specific natural products are known to modulate Ca2+ signaling pathways implicated in tumor growth, apoptosis, angiogenesis, and development of GBM. Here, the focus is on the function of Ca2+ as a therapeutic target in GBM and reviewing certain natural products that affect the signaling pathways of Ca2+.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Señalización del Calcio/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/química , Productos Biológicos/química , Neoplasias Encefálicas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glioblastoma/patología , Humanos , Estructura MolecularRESUMEN
Glioblastoma multiforme (GBM), as the most lethal brain tumor, continues to be incurable. Considering the high mortality rate of GBM, it is crucial to develop new treatment approaches. Conventional therapies, including maximal surgical resection, radiation therapy, and chemotherapy (typically temozolomide), have not led to significant changes in the survival rates of GBM patients. However, emerging modalities, such as the use of tyrosine kinase inhibitors, mTOR inhibitors, NF-κB modulators, nitrosoureas, and immunotherapeutic agents have shown promising in improving GBM outcomes. In this context, we reviewed the current status of GBM treatment, the efficacy of existing standard therapies in improving disease outcomes, and future therapeutic directions.
Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Neoplasias Encefálicas/patología , Glioblastoma/patología , Humanos , Inmunoterapia/métodos , Tasa de SupervivenciaRESUMEN
As the most popular intrinsic neoplasm throughout the brain, glioblastoma multiforme (GBM) is resistant to existing therapies. Due to its invasive nature, GBM shows a poor prognosis despite aggressive surgery and chemoradiation. Therefore, identifying and understanding the critical molecules of GBM can help develop new therapeutic strategies. Glutamatergic signaling dysfunction has been well documented in neurodegenerative diseases as well as in GBM. Inhibition of glutamate receptor activation or extracellular glutamate release by specific antagonists inhibits cell development, invasion, and migration and contributes to apoptosis and autophagy in GBM cells. This review outlines the current knowledge of glutamate signaling involvement and current therapeutic modalities for the treatment of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Glutamatos , Humanos , Invasividad Neoplásica , Transducción de SeñalRESUMEN
Glioblastoma multiforme (GBM) is the most hostile tumor in the central nervous system. Unfortunately, the prognosis of GBM patients is poor following surgical interventions, chemotherapy, and radiotherapy. Consequently, more efficient and effective treatment options for the treatment of GBM need to be explored. Zerumbone, as a sesquiterpene derived from Zingiber zerumbet Smith, has substantial cytotoxic and antiproliferative activities in some types of cancer. Here, we show that exposure of GBM cells (U-87 MG) to Zerumbone demonstrated significant growth inhibition in a concentration-dependent manner. Zerumbone also induced apoptosis and caused cell cycle arrest of human GBM U-87 MG cells in the G2/M phase of the cell cycle. In detail, the apoptotic process triggered by Zerumbone involved the upregulation of proapoptotic Bax and the suppression of antiapoptotic Bcl-2 genes expression as determined by qRT-PCR. Moreover, Zerumbone enhanced the generation of reactive oxygen species (ROS), and N-acetyl cysteine (NAC), as an antioxidant, reversed the ROS-induced cytotoxicity of U-87 MG cells. The Western blot analysis suggested that Zerumbone activated the NF-κB p65, which was partly inhibited by NAC treatment. Collectively, our results confirmed that Zerumbone induces cytotoxicity by ROS generation. Thus, the study raises the possibility of Zerumbone as a potential natural agent for treating GBM due to its ability to induce cytotoxicity.
Asunto(s)
Glioblastoma/metabolismo , Glioblastoma/patología , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Modelos Biológicos , Sesquiterpenos/química , Factores de Tiempo , Factor de Transcripción ReIA/metabolismoRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM), as the broadest cerebrum tumor, is resistant to current medical interventions, particularly chemo/radiation. Hence, it necessitates further therapeutic options that could enhance the efficacy of existing modalities. METHODS: A comprehensive and systematic review of literature on the NF-κB signaling pathway-contributed in the pathogenesis of GBM with a focus on natural products was carried out. RESULTS: Several examinations have shown that nuclear factor (NF)-κB is participated in apoptosis, cellular proliferation, angiogenesis, metastasis, invasion, and many other processes implicated in GBM pathobiology. Recent studies have provided that NF-κB regulation is the primary pharmacological target for GBM therapy. Specific natural products are involved in several signaling pathways implicated in tumor growth and apoptosis of GBM cells. CONCLUSION: In the current review, we elaborate on the role of NF-κB as a promising target in GBM and discuss some natural products affecting the NF-κB signaling pathway.
Asunto(s)
Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Humanos , Terapia Molecular Dirigida , Transducción de SeñalRESUMEN
Quercetin, a plant-derived flavonoid, is known for its antitumor and antiproliferative activities. Glioblastoma multiforme (GBM), as a highly aggressive cerebrum tumor, has a poor prognosis that is approximately 12 months despite standard therapy. Therefore, because of the low effectiveness of the current therapeutic strategies, additional medications in combination with chemotherapy and radiotherapy are needed, which could improve the prognosis of GBM patients. Multiple lines of evidence have shown that quercetin regulates many proteins involved in the cellular signal transduction in GBM. In this review, recent findings on the targeting of particular signaling pathways by quercetin and the subsequent effect on the pathogenesis of GBM are presented and discussed.
Asunto(s)
Antioxidantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Fitoquímicos/uso terapéutico , Quercetina/uso terapéutico , HumanosRESUMEN
Phosphodiesterases are a group of enzymes that hydrolyze cyclic nucleotides, which assume a key role in directing intracellular levels of the second messengers' cAMP and cGMP, and consequently cell function. The disclosure of 11 isoenzyme families and our expanded knowledge of their functions at the cell and molecular level stimulate the improvement of isoenzyme selective inhibitors for the treatment of various diseases, particularly cardiovascular diseases. Hence, future and new mechanistic investigations and carefully designed clinical trials could help reap additional benefits of natural/synthetic PDE inhibitors for cardiovascular disease in patients. This review has concentrated on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases.