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1.
Neurol India ; 69(4): 856-860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507401

RESUMO

Aim: Glioblastoma (GBM) is one of the most aggressive neoplasms of the central nervous system with dismal survival. In recent years, different variants of GBM have been described in the literature. GBM with areas of neuroectodermal differentiation (GBM-PNET) is a relatively new entity in GBM. Presence of the neuroectodermal component increases the propensity of systemic dissemination as with other intracranial primitive neuroectodermal tumors (PNET). The optimal treatment for these patients remains a controversy, with authors reporting local radiotherapy to craniospinal irradiation and chemotherapy. We intend to analyze the pattern of care for GBM with neuroectodermal component. Materials and Methods: We retrieved data of four patients with GBM-PNET treated in our institute; data were also retrieved from published series to derive treatment and outcome results. Results: In this series, we report the outcome of a series of four patients of GBM-PNET treated with adjuvant radiotherapy and temozolomide. All but one patient underwent gross total resection of the tumor. Adjuvant hypofractionated radiation with concurrent and adjuvant temozolomide was used in all cases. The median follow-up was 12.9 months in the present series. One patient experienced local recurrence 18 months after the treatment. A review of published literature on GBM-PNET was done; studies with details of patient outcome were used for an independent analysis. Twenty-three patients were identified, and the pooled analysis revealed a median progression free and overall survival of 10 and 25, months respectively. Extent of surgery, local radiation vs. craniospinal irradiation, and age at presentation had no impact on the survival. Conclusion: GBM PNET is a new entity with only few cases reported so far. Clinical behavior and treatment outcome of these tumors are not different from conventional GBM. However, these patients are at higher risk of CSF dissemination. Hence, an individualized treatment approach is best suited.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Tumores Neuroectodérmicos Primitivos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Recidiva Local de Neoplasia , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/radioterapia , Radioterapia Adjuvante , Estudos Retrospectivos , Temozolomida/uso terapêutico
2.
Mater Sci Eng C Mater Biol Appl ; 128: 112261, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474820

RESUMO

Glioblastoma multiforme (GBM) remains a major cause of mortality because treatments are precluded by to the limited transport and penetration of chemotherapeutics across the blood-brain barrier. Pitavastatin (PTV) is a hydrophobic Food and Drug Administration (FDA)-approved anticholesterolemic agent with reported anti-GBM activity. In the present study, we encapsulate PTV in silica-coated polymeric micelles (SiO2 PMs) surface-modified with the cyclic peptide Arg-Gly-Asp-Phe-Val (cRGDfV) that actively targets the αvß3 integrin overexpressed in the BBB endothelium and GBM. A central composite design is utilized to optimize the preparation process and improve the drug encapsulation ratio from 131 to 780 µg/mL. The silica shell provides full colloidal stability upon extreme dilution and enables a better control of the release kinetics in vitro with 28% of the cargo released after 12 h. Furthermore, SiO2 PMs show excellent compatibility and are internalized by human BBB endothelial cells, astrocytes and pericytes, as shown by confocal laser scanning fluorescence microscopy and flow cytometry. Finally, the anticancer efficacy is assessed in a pediatric patient-derived glioma cell line expressing high levels of the integrin subunits αv, ß3 and ß5. This PTV-loaded nanocarrier triggers apoptosis by reducing the mRNA level of anti-apoptotic genes NF-kß, IL-6, BIRC1 and BIRC5 by 89%, 33%, 81% and 63%, respectively, and the cell viability by >60%. Overall, our results suggest the potential of these hybrid nanocarriers for the targeted therapy of GBM and other tumors overexpressing integrin receptors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Criança , Células Endoteliais , Glioblastoma/tratamento farmacológico , Humanos , Integrinas , Micelas , Dióxido de Silício
3.
Mater Sci Eng C Mater Biol Appl ; 128: 112330, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474881

RESUMO

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumours. Despite advances in treatment modalities, it remains largely incurable with an extremely poor prognosis. Treatment of GBM is associated with several difficulties such as the risk of damaging healthy brain tissues during surgery, drug resistance and inadequate drug delivery across the blood brain barrier. The new nanomaterial graphene, has recently attracted great attention due to its unique physico-chemical characteristics, good biocompatibility, specific targeting and small size. Starting from simple drug delivery systems, the application of graphene-based nanomaterials has been extended to a versatile platform of multiple therapeutic modalities, including immunotherapy, gene therapy, photothermal therapy and photodynamic therapy. Graphene-based materials can also be engineered to integrate multiple functions into a single platform for combination therapy for enhanced anticancer activity and reduced side effects. This review aims to discuss the state-of-the-art applications of graphene-based materials in GBM diagnosis and therapy. In addition, future challenges and prospects regarding this promising field are discussed, which may pave the way towards improving the safety and efficacy of graphene-based therapeutics.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Grafite , Nanoestruturas , Fotoquimioterapia , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Grafite/uso terapêutico , Humanos
4.
Biomater Sci ; 9(18): 6037-6051, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34357362

RESUMO

Glioblastoma (GBM) is the most aggressive malignant brain tumor and is associated with a very poor prognosis. The standard treatment for newly diagnosed patients involves total tumor surgical resection (if possible), plus irradiation and adjuvant chemotherapy. Despite treatment, the prognosis is still poor, and the tumor often recurs within two centimeters of the original tumor. A promising approach to improving the efficacy of GBM therapeutics is to utilize biomaterials to deliver them locally at the tumor site. Local delivery to GBM offers several advantages over systemic administration, such as bypassing the blood-brain barrier and increasing the bioavailability of the therapeutic at the tumor site without causing systemic toxicity. Local delivery may also combat tumor recurrence by maintaining sufficient drug concentrations at and surrounding the original tumor area. Herein, we critically appraised the literature on local delivery systems based within the following categories: polymer-based implantable devices, polymeric injectable systems, and hydrogel drug delivery systems. We also discussed the negative effect of hypoxia on treatment strategies and how one might utilize local implantation of oxygen-generating biomaterials as an adjuvant to enhance current therapeutic strategies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Materiais Biocompatíveis/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Humanos
5.
Int J Mol Sci ; 22(15)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34361055

RESUMO

Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , Desenvolvimento de Medicamentos , Glioblastoma/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos
6.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361090

RESUMO

Glioblastoma (GBM) is a highly lethal cancer that is universally refractory to the standard multimodal therapies of surgical resection, radiation, and chemotherapy treatment. Temozolomide (TMZ) is currently the best chemotherapy agent for GBM, but the durability of response is epigenetically dependent and often short-lived secondary to tumor resistance. Therapies that can provide synergy to chemoradiation are desperately needed in GBM. There is accumulating evidence that adaptive resistance evolution in GBM is facilitated through treatment-induced epigenetic modifications. Epigenetic alterations of DNA methylation, histone modifications, and chromatin remodeling have all been implicated as mechanisms that enhance accessibility for transcriptional activation of genes that play critical roles in GBM resistance and lethality. Hence, understanding and targeting epigenetic modifications associated with GBM resistance is of utmost priority. In this review, we summarize the latest updates on the impact of epigenetic modifications on adaptive resistance evolution in GBM to therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Glioblastoma/tratamento farmacológico , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Evolução Molecular , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos
7.
Chem Biol Interact ; 347: 109622, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34375656

RESUMO

Glioblastoma multiforme (GBM) is a frequent form of malignant glioma. Strategic therapeutic approaches to treat this type of brain tumor currently involves a combination of surgery, radiotherapy and chemotherapy. Nevertheless, survival of GBM patients remains in the 12-15 months range following diagnosis. Development of novel therapeutic approaches for this malignancy is therefore of utmost importance. Interestingly, bee venom and its components have shown promising anti-cancer activities in various types of cancer even though information pertaining to GBMs have been limited. The current work was thus undertaken to better characterize the anti-cancer properties of bee venom and its components in Hs683, T98G and U373 human glioma cells. MTT-based cell viability assays revealed IC50 values of 7.12, 15.35 and 7.60 µg/mL for cell lines Hs683, T98G and U373 treated with bee venom, respectively. Furthermore, melittin treatment of these cell lines resulted in IC50 values of 7.77, 31.53 and 12.34 µg/mL, respectively. Cell viability assessment by flow cytometry analysis confirmed signs of late apoptosis and necrosis after only 1 h of treatment with either bee venom or melittin in all three cell lines. Immunoblotting-based quantification of apoptotic markers demonstrated increased expression of Bak and Bax, while Caspsase-3 levels were significantly lower when compared to control cells. Quantification by qRT-PCR showed increased expression levels of long non-coding RNAs RP11-838N2.4 and XIST in glioma cells treated with either bee venom or melittin. Overall, this study provides preliminary insight on molecular mechanisms via which bee venom and its main components can impact viability of glioma cells and warrants further investigation of its anticancer potential in gliomas.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Meliteno/uso terapêutico , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Meliteno/toxicidade , Monócitos/efeitos dos fármacos , Necrose/tratamento farmacológico , Fosfolipases A2/uso terapêutico , RNA Longo não Codificante/metabolismo , Temozolomida/uso terapêutico
8.
Mo Med ; 118(4): 346-351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373670

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive brain tumor, with median patient survival of 12-15 months even after treatment. To facilitate basic research as well as treatment development, bioengineered GBM models that adequately recapitulate aspects of the in vivo tumor microenvironment are greatly needed. Multicellular spheroids are a well-accepted model in tumor biology as well as drug screening because they recapitulate many of the solid tumor characteristics, such as hypoxic core and cell-cell communication. There are multiple approaches for growing GBM cells into tumor spheroids - non-adherent plastic dishes, hanging drop, bioreactors, and hydrogels, amongst others. Suspension spheroid models offer ease of growth, uniformity, and overall lower cost, but neglect the cell-matrix interactions, while hydrogel-based spheroids capture cell-matrix interactions and allow co-cultures with stromal cells. In this review, we summarize various approaches to fabricate GBM spheroid models as well as GBM spheroid characteristics and chemotherapeutic responsiveness as a function of hydrogel matrix encapsulation and properties, in order to advance therapies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Glioblastoma/tratamento farmacológico , Humanos , Hidrogéis , Esferoides Celulares , Microambiente Tumoral
9.
Yonsei Med J ; 62(9): 843-849, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34427071

RESUMO

PURPOSE: Temozolomide is used in first-line treatment for glioblastoma. However, chemoresistance to temozolomide is common in glioma patients. In addition, mechanisms for the anti-tumor effects of temozolomide are largely unknown. Ferroptosis is a form of programmed cell death triggered by disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. The present study was performed to elucidate the involvement of ferroptosis in the anti-tumor mechanisms of temozolomide. MATERIALS AND METHODS: We utilized the CCK8 assay to evaluate cytotoxicity. Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), iron, and glutathione (GSH) were measured. Flow cytometry and fluorescence microscope were used to detect the production of reactive oxygen species (ROS). Western blotting, RT-PCR and siRNA transfection were used to investigate molecular mechanisms. RESULTS: Temozolomide increased the levels of LDH, MDA, and iron and reduced GSH levels in TG905 cells. Furthermore, we found that ROS levels and DMT1 expression were elevated in TG905 cells treated with temozolomide and were accompanied by a decrease in the expression of glutathione peroxidase 4, indicating an iron-dependent cell death, ferroptosis. Our results also showed that temozolomide-induced ferroptosis is associated with regulation of the Nrf2/HO-1 pathway. Conversely, DMT1 knockdown by siRNA evidently blocked temozolomide-induced ferroptosis in TG905 cells. CONCLUSION: Taken together, our findings indicate that temozolomide may suppress cell growth partly by inducing ferroptosis by targeting DMT1 expression in glioblastoma cells.


Assuntos
Ferroptose , Glioblastoma , Glioblastoma/tratamento farmacológico , Humanos , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio , Temozolomida/farmacologia
10.
Nanomedicine (Lond) ; 16(20): 1775-1790, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34313137

RESUMO

Aim: To evaluate the antitumor efficacy of bevacizumab-functionalized nanocapsules in a rat glioblastoma model after the pretreatment with nanocapsules functionalized with a peptide-specific to the epidermal growth factor receptor variant III. Materials & methods: Nanocapsules were prepared, physicochemical characterized and intranasally administered to rats. Parameters such as tumor size, histopathological characteristics and infiltration of CD8+ T lymphocytes were evaluated. Results: The strategy of treatment resulted in a reduction of 87% in the tumor size compared with the control group and a higher infiltration of CD8+ T lymphocytes in tumoral tissue. Conclusion: The block of two different molecular targets using nose-to-brain delivery represents a new and promising approach against glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanocápsulas , Animais , Bevacizumab/uso terapêutico , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Receptores ErbB , Glioblastoma/tratamento farmacológico , Nanocápsulas/uso terapêutico , Peptídeos/uso terapêutico , Ratos
11.
Colloids Surf B Biointerfaces ; 206: 111946, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34216850

RESUMO

The aim of this study was the preparation of solid lipid nanoparticles (SLN) formed from cetyl palmitate with having targeting molecules for monocarboxylate transporter-1 (MCT-1): ß-hydroxybutyric acid and anticancer agents: carmustine (BCNU) and temozolomide (TMZ) for enhanced anti-proliferation against glioblastoma multiforme (GBM). Properties including size, morphology, chemical structure, zeta potential, drug encapsulation efficacy, drug release, biocompatibility, stability were determined, and in vitro studies were done. BCNU and TMZ loaded SLNs had a hydrodynamic size of 227 nm ± 46 a zeta potential of -25 mV ± 4 with biocompatible features. The data showed rapid drug release at first and then continuous release. Nanoparticles could be stored for nine months. BCNU and TMZ loaded SLNs exhibited a remarkable increment in the antitumor activity compared to the free-drugs and induced apoptosis on U87MG cells. In addition, targeted nanoparticles were more uptaken by MCT-1 expressing brain cells. This study indicated that BCNU and TMZ loaded SLNs could act as a useful anticancer system for targeted GBM therapy.


Assuntos
Glioblastoma , Nanopartículas , Preparações Farmacêuticas , Encéfalo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Lipídeos
12.
J Enzyme Inhib Med Chem ; 36(1): 1541-1552, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238111

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Quinases da Família src/metabolismo
13.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203727

RESUMO

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB).


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Animais , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Evasão da Resposta Imune
14.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205043

RESUMO

Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Glioblastoma/metabolismo , Animais , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Lipossomos , Camundongos , Estrutura Molecular , Invasividade Neoplásica
15.
Oncoimmunology ; 10(1): 1940673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290904

RESUMO

Introduction: Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure. Methods: Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays. Results: Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 (P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment. Conclusions: Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.


Assuntos
Glioblastoma , Glioma , Animais , Glioblastoma/tratamento farmacológico , Imunossupressão , Imunoterapia , Linfonodos , Camundongos
16.
Nat Commun ; 12(1): 4228, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244484

RESUMO

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/patologia , Desoxiadenosinas/metabolismo , Glioblastoma/genética , Purina-Núcleosídeo Fosforilase/deficiência , Tionucleosídeos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/metabolismo , Desoxiadenosinas/análise , Feminino , Secções Congeladas , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Homozigoto , Humanos , Metabolômica , Metionina Adenosiltransferase/metabolismo , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Proteína-Arginina N-Metiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/genética , Deleção de Sequência , Tionucleosídeos/análise , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 41(7): 3337-3341, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230129

RESUMO

BACKGROUND/AIM: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive type of primary brain tumor and a cornerstone in its treatment is radiotherapy (RT). However, RT for GBM is largely ineffective at clinically safe doses, thus, the study of radiosensitizers is of great significance. MATERIALS AND METHODS: With accumulating evidence for the anticancer effect of compounds from cranberry, this study was designed to investigate if cranberry extract (CE) sensitizes GBM to RT in the widely used human glioblastoma cell line U87. We utilized clonogenic survival assays, cell proliferation assays, and caspase-3 activity kits. Potential proliferative and apoptotic molecular mechanisms were evaluated by reverse transcription-polymerase chain reaction. RESULTS: We found that CE alone had little effect on the survival of U87 cells. However, RT supplemented by CE significantly inhibited proliferation and promoted apoptosis of U87 cells when compared with RT alone. The proliferation-inhibitory effect of RT/CE might be attributable to the up-regulation of p21, along with the down-regulation of cyclin B and cyclin-dependent kinase 4. This pro-apoptotic effect might additionally be attributable to the down-regulation of survivin. CONCLUSION: These results warrant further study of the potential radiosensitizing capacity of CE in glioblastoma and other cancer types.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Extratos Vegetais/farmacologia , Radiossensibilizantes/farmacologia , Vaccinium macrocarpon/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Regulação para Cima/efeitos dos fármacos
18.
Talanta ; 233: 122570, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215066

RESUMO

Lipids differences between tumor and normal tissue have been proved to be of diagnostic and therapeutic significance. The research of lipidomics in tumor is more and more important. Mass spectrometry like matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) can be more convenient and informative for lipids researching in biological and clinical researches. Most of malignant tumors like glioblastoma are characterized by incomplete differentiation, so differentiation therapy has made important progress in tumor treatment. Lipid profiles changes after therapy are worthy investigating. In our study, glioblastoma cell line U87-MG cells were treated by inducers of sodium phenylbutyrate (SPB) and all-trans retinoic acid (ATRA). The changes in lipids on cell membrane were profiled by MALDI-MS. The differentiation degree was assessed by cell proliferation, cell cycle, morphology and protein expression before MALDI-MS analysis. Comparing the inducer treated and untreated U87-MG cells, reduced proliferation rate, blocked cell cycle, benign nucleus morphology and changed expression of protein CD133 and glial fibrillary acidic protein (GFAP), were found after drug treatment. Moreover, the lipids of cell membrane presented distinguished differences in the drug treated cells. Most of the glycerophosphocholines (PC) with an increasing abundance are unsaturated PCs (PC (38:1), 816 m/z; PC (36:1), 788 m/z; PC (31:1), 725 m/z), and those decreasing are saturated PCs (PC (32:0), 734 m/z). These results provide the lipidomic differentiation which may be a significant guidance for evaluating the therapeutic effect of tumor therapy.


Assuntos
Glioblastoma , Preparações Farmacêuticas , Diferenciação Celular , Glioblastoma/tratamento farmacológico , Humanos , Lipidômica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
J Coll Physicians Surg Pak ; 31(8): 932-936, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34320710

RESUMO

OBJECTIVE: To evaluate the predictive significance of the duration of temozolomide (TMZ) in patients with glioblastoma multiforme (GBM) who were treated with bevacizumab (Beva) as second-line setting. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Bezmialem Vakif University School of Medicine Hospital, Istanbul, Turkey, from January 2014 to September 2020. METHODOLOGY: A total of 109 patients, 47 (43.1%) females and 62 (56.9%) males, were retrospectively included in the study. All patients received TMZ as first-line and Beva as second-line treatment. Kaplan-Meier method and Cox regression model were performed for survival and univariate/multivariate analyses, respectively. RESULTS: Patients treated with first-line TMZ were divided into two groups according to the PFS. Group 1 is <9 months and group 2 is ≥9 months. Overall survival (OS) of group 1 and group 2 patients was evaluated  after the initiation of second-line bevacizumab treatment. The OS in group 1 was 7.8 months (6.9-8.6, 95% CI), and group 2 was eight months (6.4-9.5, 95% CI), but it was statistically non-significant (p = 0.837). CONCLUSION: Duration of first-line TMZ treatment was not a predictor for OS of the GBM patients, who were treated with Beva as second-line setting. Key Words: Bevacizumab, Duration of treatment, Glioblastoma multiforme, Predictive score, Temozolomide.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Estudos Retrospectivos , Temozolomida/uso terapêutico , Turquia/epidemiologia
20.
Cancer Invest ; 39(8): 627-644, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34254870

RESUMO

Glioblastoma (GB) is the most lethal form of primary brain neoplasm. TMZ is the first-line standard treatment, but the strong resistance constrains the efficacy in clinical use. GB contains glioma stem cells (GSCs), which contribute to TMZ resistance, promote cell survival evolvement, and repopulate the tumor mass. This review summarizes the TMZ-resistance mechanisms and discusses several potential therapies from the conservative opinion of GSC-targeted therapy orientation to the current view of TMZ resistance-aimed efficacy, which will provide an understanding of the role of heterogeneity in drug resistance and improve therapeutic efficacy in general.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Humanos , Temozolomida/farmacologia
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