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1.
Adv Exp Med Biol ; 1234: 107-122, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040858

RESUMO

Glioblastoma (GBM) develops from adult brain white matter and is the most common and lethal primary brain tumor, characterized by rapid growth and invasion. GBM tumors frequently spread into the contralateral hemisphere, including in the beginning of tumor development. However, after complete resection of the tumor mass and chemo-radiotherapy, GBM commonly recurs around the tumor removal site, suggesting that the microenvironment at the tumor border provides therapeutic resistance to GBM cells. To improve patient prognosis, understanding the microenvironment at the tumor border is critical. Several microRNAs (miRNAs) show higher expression at the tumor border, with the top three involved in oligodendrocyte differentiation. Oligodendrocyte progenitor cells (OPCs) may induce stemness and chemo-radioresistance in GBM cells, providing a supportive function to promote GBM. This review describes important features of OPCs and insights into the "border niche," a unique microenvironment that allows GBM cells to survive and recur at the tumor border.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células Precursoras de Oligodendrócitos/patologia , Microambiente Tumoral , Humanos
2.
Anticancer Res ; 40(1): 213-220, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892569

RESUMO

BACKGROUND/AIM: Kisspeptin produced from the KISS1 gene is secreted from the living cells, binds to endogenous receptor KISS1R (also called G protein-coupled receptor 54, GPR54), and has various functions in normal physiological conditions. Although an anti-metastatic role of kisspeptin in cancer is well known in several cancer types, its role in brain tumors is not yet understood. Herein, we investigated a the role of kisspeptin in glioblastoma cells. MATERIALS AND METHODS: Glioblastoma cells were treated with kisspeptin and subjected to proliferation, migration, and invasion assays. KISS1R dependency was tested by KISS1R silencing with KISS1R siRNAs. RESULTS: Kisspeptin inhibited migratory and invasive abilities of U87-MG, U-251-MG and U373-MG glioblastoma cells with no effect on cell viability. KISS1R gene silencing with KISS1R siRNAs blocked kisspeptin-induced glioblastoma cell invasiveness. Moreover, chemical inhibitors against Gq, PLC or PKC blocked kisspeptin-induced glioblastoma cell invasiveness. CONCLUSION: Kisspeptin induces glioblastoma cell invasiveness via the KISS1R-Gq-PLC-PKC signaling pathway.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Kisspeptinas/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Fosfolipases Tipo C/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Invasividade Neoplásica , Metástase Neoplásica
3.
World Neurosurg ; 133: e640-e645, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31568907

RESUMO

BACKGROUND: Concomitant chemoradiation (CCRT) after surgical resection has been established as standard care for patients with newly diagnosed glioblastoma (GBM). However, the optimal time interval from surgery to starting CCRT (IST) remains controversial. METHODS: The electronic medical records of 160 patients with newly diagnosed GBM treated at our institution between 2009 and 2016 were examined retrospectively. The eligibility criteria were newly diagnosed GBM, pathology confirmed by craniotomy or stereotactic biopsy, and CCRT performed in our institution. Patients who received CCRT within 28 days after surgery were defined as the early group, and those who received CCRT at >28 days after surgery were defined as the delayed group. RESULTS: We included 138 patients who met our eligibility criteria. The median IST was 26 days (range, 10-55 days). In a Kaplan-Meier analysis, overall survival (OS) did not differ between groups (15.5 month for the early group vs. 14.5 months for the delayed group; P = 0.707). In the gross total resection (GTR) subgroup, OS did not differ significantly (20.0 months for the early vs. 21.0 months for the delayed group; P = 0.854). In the non-GTR subgroup, however, the early group had better OS than the delayed group (11.0 months vs. 5.0 months; P = 0.029). CONCLUSIONS: Performing CCRT within versus after 28 days after surgery did not result in a statistically significant difference in OS. However, a subgroup analysis showed that delayed CCRT may be associated with worse OS in the non-GTR group.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Procedimentos Neurocirúrgicos/métodos , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimiorradioterapia/mortalidade , Intervalo Livre de Doença , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
4.
World Neurosurg ; 133: e583-e591, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31561040

RESUMO

OBJECTIVE: To assess the prognostic profile, clinical outcome, treatment-associated morbidity, and treatment burden of elderly patients with glioblastoma (GBM) undergoing microsurgical tumor resection as part of contemporary treatment algorithms. METHODS: We retrospectively identified patients with GBM ≥65 years of age who were treated by resection at 2 neuro-oncology centers. Survival was assessed by Kaplan-Meier analyses; log-rank tests identified prognostic factors. RESULTS: The study population included 160 patients (mean age, 73.1 ± 5.1 years), and the median contrast-enhancing tumor volume was 31.0 cm3. Biomarker analyses revealed O(6)-methylguanine-DNA methyltransferase-promoter methylation in 62.7% and wild-type isocitrate dehydrogenase in 97.5% of tumors. The median extent of resection (EOR) was 92.3%, surgical complications were noted in 10.0% of patients, and the median postoperative hospitalization period was 8 days. Most patients (60.0%) received adjuvant radio-/chemotherapy. The overall treatment-associated morbidity was 30.6%. The median progression-free and overall survival were 5.4 months (95% confidence interval [CI], 4.6-6.4 months) and 10.0 months (95% CI, 7.9-11.7 months). The strongest predictors for favorable outcome were patient age ≤73.0 years (P = 0.0083), preoperative Karnofsky Performance Status Scale score ≥80% (P = 0.0179), postoperative modified Rankin Scale score ≤1 (P < 0.0001), adjuvant treatment (P < 0.0001), and no treatment-associated morbidity (P = 0.0478). Increased EOR did not correlate with survival (P = 0.5046), but correlated significantly with treatment-associated morbidity (P = 0.0031). CONCLUSIONS: Clinical outcome for elderly patients with GBM remains limited. Nonetheless, the observed treatment-associated morbidity and treatment burden were moderate in the patients, and patient age and performance status remained the strongest predictors for survival. The risks and benefits of tumor resection in the age of biomarker-adjusted treatment concepts require further prospective evaluation.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Procedimentos Neurocirúrgicos , Idoso , Idoso de 80 Anos ou mais , Áustria , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
5.
Oncology ; 98(1): 16-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31514200

RESUMO

PURPOSE: Preclinical studies indicated that imatinib may have single-agent activity in glioblastoma through inhibition of tyrosine kinase activity and also that it might enhance the efficacy of radiotherapy. We therefore sought to investigate clinical efficacy in patients with newly diagnosed and recurrent glioblastoma in combination with radiotherapy. METHODS: We conducted a nonrandomized, 2-arm, open-label phase II trial including patients aged 18 years or older with an ECOG performance status of 0-2 that were either newly diagnosed (arm A) with a measurable tumor (i.e., after incomplete resection or biopsy) or that were diagnosed with progression of a glioblastoma after initial therapy (arm B). Patients in arm A received 600 mg/day imatinib in combination with hypofractionated radiotherapy (2.5 Gy per fraction, 22 fractions). Patients in arm B received 600 mg/day imatinib alone or in combination with re-irradiation at various doses. In case tumor progression occurred, CCNU was added (2 cycles, 100 mg/m2) to imatinib. The primary end point was progression-free survival (PFS). The secondary end point was safety, defined as per Common Terminology Criteria for Adverse Events (version 2.0). Overall survival (OS) was analyzed as an exploratory end point. RESULTS: Fifty-one patients were enrolled, of which 19 were included in arm A and 32 in arm B. The median follow-up was 4 (0.5-30) months in arm A and 6.5 (0.3-51.5) months in arm B. The median PFS was 2.8 months (95% CI 0-8.7) in arm A and 2.1 months (95% CI 0-11.8) in arm B. The median OS was 5.0 (0.8-30) months (95% CI 0-24.1) in arm A and 6.5 (0.3-51.5) months (95% CI 0-32.5) in arm B. The major grade 3 events were seizure (present in 17 patients), pneumonia (11 patients), and vigilance decrease (7 patients). CONCLUSIONS: Imatinib showed no measurable activity in patients with newly diagnosed or recurrent glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biópsia , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Glioblastoma/mortalidade , Glioblastoma/cirurgia , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Cuidados Pós-Operatórios , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Retratamento , Resultado do Tratamento
6.
J Cancer Res Clin Oncol ; 146(1): 117-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31844979

RESUMO

PURPOSE: Glioblastoma multiforme (GBM) is a poorly curable disease due to its profound chemoresistance. Despite recent advances in surgery, radiotherapy and chemotherapy, the efficient treatment of GBMs is still a clinical challenge. Beside others, AT101, the R-(-) enantiomer of gossypol, and demethoxycurcumin (DMC), a curcumin-related demethoxy compound derived from Curcuma longa, were considered as possible alternative drugs for GBM therapy. METHODS: Using different human primary GBM cell cultures in a long-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 5 µM AT101 and 5 µM or 10 µM DMC were investigated. Furthermore, western blots on pAkt and pp44/42 as well as JC-1 staining and real-time RT-PCR were performed to understand the influence of the treatment at the molecular and gene level. RESULTS: Due to enhanced anti-proliferative effects, we showed that combined therapy with both drugs was superior to a single treatment with AT101 or DMC. Here, by determination of the combination index, a synergism of the combined drugs was detectable. Phosphorylation and thereby activation of the kinases p44/42 and Akt, which are involved in proliferation and survival processes, were inhibited, the mitochondrial membrane potential of the GBM cells was altered, and genes involved in dormancy-associated processes were regulated by the combined treatment strategy. CONCLUSION: Combined treatment with different drugs might be an option to efficiently overcome chemoresistance of GBM cells in a long-term treatment strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diarileptanoides/farmacologia , Glioblastoma/tratamento farmacológico , Gossipol/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Gossipol/administração & dosagem , Gossipol/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
7.
An Acad Bras Cienc ; 91(4): e20191031, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800712

RESUMO

Diosmin is a flavone glycoside clinically used as the main component of Daflon for the treatment of venous diseases. Several studies demonstrated that this natural compound can induce apoptosis in different tumors. However, isolated diosmin has not been studied regarding its effects on glioblastoma so far. Since glioblastoma is a highly lethal and fast-growing brain tumor, new therapeutic strategies are urgently needed. Herein, we evaluated the role of this flavonoid against glioblastoma cells using in vitro assays. Diosmin significantly reduced the viability of GBM95, GBM02, and U87MG glioblastoma cells, but not of healthy human astrocytes, as verified by MTT assay. Vimentin immunostaining showed that diosmin induced morphological changes in GBM95 and GBM02 cells, making them smaller and more polygonal. Diosmin did not inhibit GBM95 and GBM02 cell proliferation, but it caused DNA fragmentation, as verified by the TUNEL assay, and increased cleaved caspase-3 expression in these cells. In summary, diosmin is able to induce caspase-dependent apoptosis specifically in tumor cells and, therefore, could be considered a promising therapeutic compound against glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Diosmina/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos
8.
Anticancer Res ; 39(12): 6743-6750, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810939

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumour. The interaction between high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is important for tumour cell growth. Previously, we identified an anticancer candidate, papaverine, that inhibited the HMGB1-RAGE interaction. MATERIALS AND METHODS: Our study assessed the anticancer effects of papaverine alone or in combination with temozolomide on U87MG and T98G human GBM cells using clonogenicity assays, as well as in a U87MG xenograft mouse model. The radiosensitizing efficacy of papaverine was measured based on the clonogenicity of T98G cells. RESULTS: Papaverine significantly inhibited the clonogenicity of U87MG and T98G cells. Compared with single treatment, the combination of papaverine and temozolomide more highly suppressed the clonogenicity of T98G cells and delayed tumour growth in the U87MG xenograft mouse model. Furthermore, papaverine increased the radiosensitivity of T98G cells. CONCLUSION: Papaverine is a potential anticancer drug in GBM treatment.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Papaverina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/radioterapia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tolerância a Radiação/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Adv Exp Med Biol ; 1190: 281-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760651

RESUMO

Gliomas are a heterogeneous group of tumors with evolving classification based on genotype. Isocitrate dehydrogenase (IDH) mutation is an early event in the formation of some diffuse gliomas, and is the best understood mechanism of their epigenetic dysregulation. Glioblastoma may evolve from lower-grade lesions with IDH mutations, or arise independently from copy number changes in platelet-derived growth factor receptor alpha (PDGFRA) and phosphatase and tensin homolog (PTEN). Several molecular subtypes of glioblastoma arise from a common proneural precursor with a tendency toward transition to a mesenchymal subtype. Following oncogenic transformation, gliomas escape growth arrest through a distinct step of aberrant telomere reverse transcriptase (TERT) expression, or mutations in either alpha thalassemia/mental retardation syndrome (ATRX) or death-domain associated protein (DAXX) genes. Metabolic reprogramming allows gliomas to thrive in harsh microenvironments such as hypoxia, acidity, and nutrient depletion, which contribute to tumor initiation, maintenance, and treatment resistance.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Glioma/patologia , Reprogramação Celular , Humanos , Isocitrato Desidrogenase/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Telomerase/genética , Microambiente Tumoral , Proteína Nuclear Ligada ao X/genética
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 817-822, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750824

RESUMO

Objective To investigate the role of RAD51 in cell proliferation, migration and chemosensitivity to temozolomide (TMZ) using U251 glioma cell line, and to clarify the underlying molecular mechanism. Methods TCGA database was utilized to analyze the expression changes of RAD51 in gliomas. RAD51 was over-expressed or knocked down in U251 glioma cells via lentivirus infection, or its activity was inhibited by small molecule inhibitors. Cell proliferation and migration ability were examined by CCK-8 assay, colony formation assay, and scratch wound-healing assay; CCK-8 assay and flow cytometry were performed to assess the effect of RAD51 on the sensitivity of glioma cells upon the treatment of temozolomide. Western blotting was used to determine the alteration of P53. Results The expression of RAD51 significantly increased in glioma tissues. RAD51 enhanced the proliferation and migration ability of U251 glioma cells; knockdown of RAD51 enhanced the sensitivity of U251 glioma cells to temozolomide. Over-expression of RAD51 increased the expression of P53, whereas knockdown of RAD51 decreased the expression of P53. Conclusion RAD51 plays an oncogene function in glioma cells. RAD51 over-expression enhances the proliferation and migration of glioma cells. RAD51 knockdown increases the sensitivity of glioma cells to temozolomide.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Proliferação de Células , Glioblastoma/patologia , Rad51 Recombinase/metabolismo , Temozolomida/farmacologia , Apoptose , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos
12.
Anticancer Res ; 39(11): 5983-5990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704823

RESUMO

BACKGROUND/AIM: DJ-1, an oncogenic molecule, helps to maintain somatic stem cells by reducing the intracellular level of reactive oxygen species (ROS). This study investigated the role of DJ-1 in glioma stem cells (GSCs). MATERIALS AND METHODS: U87-MG (U87) and U251-MG (U251) glioblastoma cell lines that express wild-type and mutant p53, respectively, were used. These were cultured with DJ-1-targeting siRNA and subjected to a variety of in vitro experiments or intracranial transplantation into nude mice. RESULTS: Knockdown of DJ-1 reduced clonogenicity only in U87 cells, which was rescued by p53 depletion. ROS accumulated in DJ-1-depleted cells, although treatment with N-acetyl cysteine, which quenches ROS, did not affect exhaustion of CSCs among U87 cells by DJ-1 knockdown. In a serial transplantation study, DJ-1 knockdown prolonged the survival of mice in secondary transplantation. CONCLUSION: DJ-1 plays a pivotal role in maintenance of stem cell self-renewal in the U87 cell line.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Autorrenovação Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteína Desglicase DJ-1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteína Desglicase DJ-1/antagonistas & inibidores , Proteína Desglicase DJ-1/genética , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Anticancer Res ; 39(11): 6073-6086, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704835

RESUMO

BACKGROUND/AIM: Oncolytic adenoviruses are promising therapeutic agents against both the bulk of tumor cells and cancer stem cells. The present study intended to test the oncolytic capability of adenovirus serotype 6 (Ad6), which has a lower seroprevalence and hepatotoxicity relatively to adenovirus 5 (Ad5), against the glioblastoma and its cancer stem cells. MATERIALS AND METHODS: Oncolytic efficacy of Ad6 was compared to widespread Ad5 both in vitro and in vivo, using the U87 and U251 human glioblastoma cell lines and subcutaneously transplanted U87 cells in SCID mice, respectively. RESULTS: Ad6 had a dose-dependent cytotoxicity toward glioblastoma cells in vitro and its intratumoral injections lead to a significant (p<0.05) decrease in volume of U87 xenografts, similarly to Ad5. Based on the innate capability of glioblastoma cancer stem cells to internalize a fluorescent-labeled double-stranded DNA probe, the spatial localization of these cells was estimated and it was shown that the number of cancer stem cells tended to decrease under adenovirus therapy as compared to the control group. CONCLUSION: Ad6 was shown to be a promising agent for treating glioblastomas.


Assuntos
Adenovírus Humanos/genética , Glioblastoma/terapia , Células-Tronco Neoplásicas/metabolismo , Terapia Viral Oncolítica , Replicação Viral , Adenovírus Humanos/classificação , Animais , Apoptose , Proliferação de Células , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/virologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Photochem Photobiol B ; 201: 111640, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734545

RESUMO

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase and heme oxygenase-1 and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).


Assuntos
Corantes Fluorescentes/química , Microscopia Confocal , Protoporfirinas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Corantes Fluorescentes/metabolismo , Genisteína/metabolismo , Genisteína/farmacologia , Glioblastoma/patologia , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/metabolismo , Humanos , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Metaloporfirinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Protoporfirinas/metabolismo , Protoporfirinas/farmacologia
15.
Expert Opin Investig Drugs ; 28(12): 1041-1049, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31726894

RESUMO

Introduction: High-grade gliomas (HGG) are extremely aggressive brain malignancies that are fatal. Despite maximal resection, chemotherapy, and radiation, these tumors inevitably recur and present a poor median overall survival (mOS); hence a pressing need for improved treatments.Areas covered: This review assesses DNX-2401 as a treatment of recurrent HGG. Phase I data on efficacy, safety, and tolerability are examined while insights and perspectives on future directions are offered.Expert opinion: This phase I study assessed DNX-2401 in two study groups; one received an intratumoral injection without tumor resection while the second received an intratumoral injection followed by surgical resection 14 days later with a second injection into the resection cavity. In patients that did not receive resection, the mOS was 9.5 months while patients in the resection group had a mOS of 13 months, a promising extension of survival compared to historical controls. Furthermore, this study had numerous long-term survivors living for greater than 2 years. DNX-2401 was well tolerated with no Grade 3/4 adverse events; it provoked an immunologic response to the tumor which may contribute to the complete responses in some patients. Randomized-control trials are necessary and further studies are warranted to identify patients who will benefit most.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia Viral Oncolítica/métodos , Adenoviridae , Animais , Neoplasias Encefálicas/patologia , Drogas em Investigação/administração & dosagem , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos , Taxa de Sobrevida
17.
Life Sci ; 236: 116917, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614149

RESUMO

AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , NF-kappa B/metabolismo , Fatores de Transcrição NFI/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , NF-kappa B/genética , Fatores de Transcrição NFI/genética , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Radiol Clin North Am ; 57(6): 1199-1216, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582045

RESUMO

Radiographic monitoring of posttreatment glioblastoma is important for clinical trials and determining next steps in management. Evaluation for tumor progression is confounded by the presence of treatment-related radiographic changes, making a definitive determination less straight-forward. The purpose of this article was to describe imaging tools available for assessing treatment response in glioblastoma, as well as to highlight the definitions, pathophysiology, and imaging features typical of true progression, pseudoprogression, pseudoresponse, and radiation necrosis.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Diagnóstico por Imagem/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Lesões por Radiação/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Progressão da Doença , Glioblastoma/patologia , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Imagem Multimodal , Necrose , Tomografia por Emissão de Pósitrons , Lesões por Radiação/patologia
19.
Chem Biol Interact ; 314: 108849, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610157

RESUMO

To provide novel insight into approaches designed to combat glioblastoma, the molecular details of the cytotoxicity of gamabufotalin, were investigated in the human glioblastoma cell line U-87. A dose-dependent cytotoxicity was observed in the cells, whereas no detectable toxicity was confirmed in mouse primary astrocytes. LDH leakage was only observed in the cells treated with a relatively high concentration (>80 ng/ml). Downregulation of the expression levels of Aurora B, cdc25A, cdc25C, cdc2, Cyclin B1 and survivin, and upregulation of the expression level of p21 were observed in treated cells and occurred in parallel with G2/M phase arrest. Treatment with gamabufotalin also downregulated the expression level of uPA, CA9, and upregulated the expression level of TIMP3, all of which are closely associated with invasion/metastasis. Autophagy induction was observed in the treated cells and the addition of wortmannin, a potent autophagy inhibitor, significantly rescued U-87 cells. These results indicate that gamabufotalin exhibits cytotoxicity against cancerous glial cells with high potency and selectivity through multiple cytotoxic signaling pathways. The activation of p38 MAPK pathway along with the upregulation of VEGF/VEGFR2 was observed in the treated cells, both of which are likely to be compensatory changes in response to gamabufotalin treatment. Intriguingly, a specific inhibitor of p38 MAPK enhanced the cytotoxicity of the drug, suggesting an important prosurvival role for p38 MAPK. We thus suggest that developing a new combination regimen of gamabufotalin plus a p38 MAPK inhibitor and/or inhibitors for VEGF/VEGFR could improve the efficacy of the drug, and may provide more therapeutic benefits to patients with glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Autofagia/efeitos dos fármacos , Bufanolídeos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Wortmanina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Adv Exp Med Biol ; 1167: 207-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520357

RESUMO

Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Genomic amplifications, activating mutations, and overexpression of receptor tyrosine kinases (RTKs) such as EGFR, and genes in core RTK signaling transduction pathways such as PI3K are common in GBM. However, efforts to target these pathways have been largely unsuccessful in the clinic, and the median survival of GBM patients remains poor at 14-15 months. Therefore, to improve patient outcomes, there must be a concerted effort to elucidate the underlying biology involved in GBM tumorigenesis. Drosophila melanogaster has been a highly effective model for furthering our understanding of GBM tumorigenesis due to a number of experimental advantages it has over traditional mouse models. For example, there exists extensive cellular and genetic homology between humans and Drosophila, and 75% of genes associated with human disease have functional fly orthologs. To take advantage of these traits, we developed a Drosophila GBM model with constitutively active variants of EGFR and PI3K that effectively recapitulated key aspects of GBM disease. Researchers have utilized this model in forward genetic screens and have expanded on its functionality to make a number of important discoveries regarding requirements for key components in GBM tumorigenesis, including genes and pathways involved in extracellular matrix signaling, glycolytic metabolism, invasion/migration, stem cell fate and differentiation, and asymmetric cell division. Drosophila will continue to reveal novel biological pathways and mechanisms involved in gliomagenesis, and this knowledge may contribute to the development of effective treatment strategies to improve patient outcomes.


Assuntos
Neoplasias Encefálicas/patologia , Drosophila melanogaster , Glioblastoma/patologia , Adulto , Animais , Transformação Celular Neoplásica , Modelos Animais de Doenças , Humanos , Camundongos , Transdução de Sinais
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