RESUMEN
BACKGROUND: The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree. RESULTS: In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent bloodâbrain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects. CONCLUSION: Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Liposomas , Ratones Desnudos , ARN Interferente Pequeño , Verteporfina , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Liposomas/química , Verteporfina/farmacología , Verteporfina/uso terapéutico , Animales , Humanos , Línea Celular Tumoral , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas Señalizadoras YAP , Nanopartículas/química , Ratones Endogámicos BALB C , Factores de Transcripción/metabolismo , Angiomotinas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , PéptidosRESUMEN
Gender plays a crucial role in the occurrence and development of cancer, as well as in the metabolism of nutrients and energy. Men and women display significant differences in the incidence, prognosis, and treatment response across various types of cancer, including certain sex-specific tumors. It has been observed that male glioma patients have a higher incidence and worse prognosis than female patients, but there is currently a limited systematic evaluation of sex differences in gliomas. The purpose of this study is to provide an overview of the association between fluctuations in sex hormone levels and changes in their receptor expression with the incidence, progression, treatment, and prognosis of gliomas. Estrogen may have a protective effect on glioma patients, while exposure to androgens increases the risk of glioma. We also discussed the specific genetic and molecular differences between genders in terms of the malignant nature and prognosis of gliomas. Factors such as TP53, MGMT methylation status may play a crucial role. Therefore, it is essential to consider the gender of patients while treating glioma, particularly the differences at the hormonal and molecular levels. This approach can help in the adoption of an individualized treatment strategy.
Asunto(s)
Neoplasias Encefálicas , Glioma , Hormonas Esteroides Gonadales , Humanos , Glioma/epidemiología , Glioma/genética , Glioma/patología , Glioma/metabolismo , Femenino , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Factores Sexuales , Hormonas Esteroides Gonadales/metabolismo , Pronóstico , Incidencia , Factores de Riesgo , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismoRESUMEN
Chemotherapy of glioblastoma (GBM) has not yielded success due to inefficient blood-brain barrier (BBB) penetration and poor glioma tissue accumulation. Aerobic glycolysis, as the main mode of energy supply for GBM, safeguards the rapid growth of GBM while affecting the efficacy of radiotherapy and chemotherapy. Therefore, to effectively inhibit aerobic glycolysis, increase drug delivery efficiency and sensitivity, a novel temozolomide (TMZ) nanocapsule (ApoE-MT/siPKM2 NC) is successfully designed and prepared for the combined delivery of pyruvate kinase M2 siRNA (siPKM2) and TMZ. This drug delivery platform uses siPKM2 as the inner core and methacrylate-TMZ (MT) as the shell component to achieve inhibition of glioma energy metabolism while enhancing the killing effect of TMZ. By modifying apolipoprotein E (ApoE), dual targeting of the BBB and GBM is achieved in a "two birds with one stone" style. The glutathione (GSH) responsive crosslinker containing disulfide bonds ensures "directional blasting" cleavage of the nanocapsules to release MT and siPKM2 in the high GSH environment of glioma cells. In addition, in vivo experiments verify that ApoE-MT/siPKM2 NC has good targeting ability and prolongs the survival of tumor-bearing nude mice. In summary, this drug delivery system provides a new strategy for metabolic therapy sensitization chemotherapy.
Asunto(s)
Glioblastoma , Glucólisis , Nanocápsulas , Temozolomida , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Animales , Temozolomida/farmacología , Temozolomida/química , Nanocápsulas/química , Ratones , Línea Celular Tumoral , Glucólisis/efectos de los fármacos , Humanos , Ratones Desnudos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , ARN Interferente Pequeño/metabolismo , Barrera Hematoencefálica/metabolismo , Glutatión/metabolismo , Glutatión/químicaRESUMEN
As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514.
Asunto(s)
Quimiocina CCL3 , Progresión de la Enfermedad , Glioma , Estrés Psicológico , Microambiente Tumoral , Animales , Humanos , Masculino , Ratones , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Quimiocina CCL3/metabolismo , Glioma/inmunología , Glioma/metabolismo , Glioma/patología , Glioma/tratamiento farmacológico , Ratones Endogámicos C57BL , Estrés Psicológico/inmunología , Estrés Psicológico/complicaciones , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM. METHODS: The synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. RESULTS: Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity. CONCLUSION: Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials. Video Abstract.
Asunto(s)
Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Receptores ErbB/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Línea Celular Tumoral , Proliferación CelularRESUMEN
The antisense transcript of SATB2 protein (SATB2-AS1) is a novel long non-coding RNA (lncRNA) which is involved in the development of colorectal cancer, breast cancer and hepatocellular carcinoma. In the present study, it was aimed to investigate the consequent situation of SATB2-AS1 in tissue and cell lines of glioma. The expression of SATB2-AS1 in glioma cases was analyzed in The Cancer Genome Atlas datasets. The glycolytic metabolism was determined in glioma cells by detection of extracellular glucose level, oxygen consumption rate and extracellular acidification rate. Cell Counting Kit-8 assay and flow cytometry were used to assess cell proliferation and apoptosis in glioma cells. The interaction between SATB2-AS1 and microRNA (miR)-671-5p was verified by bioinformatic analysis, reverse transcription-quantitative PCR, dual luciferase reporter assay and RNA immunoprecipitation assay. The expression levels of the downstream targets of SATB2-AS1 were studied by western blotting. Results demonstrated that SATB2-AS1 was a downregulated lncRNA in low grade glioma and glioblastoma. Gain-of-function assay demonstrated that SATB2-AS1 inhibited cell proliferation, and glycolytic metabolism, while induced cell apoptosis in glioma cells. SATB2-AS1 sponged and suppressed the expression of an oncogenic miRNA miR-671-5p. By regulation of miR-671-5p, SATB2-AS1 upregulated cerebellar degeneration related protein 1 (CDR1) and Visinin-like 1 (VSNL1) expression in glioma cells. miR-671-5p overexpression partially reversed the antitumor effect of SATB2-AS1 in glioma. In conclusion, the current study demonstrated that there was a downregulation of SATB2-AS1 in glioma, and SATB2-AS1 regulated miR-671-5p/CDR1 axis and miR-671-5p/VSNL1 axis in glioma.
RESUMEN
BACKGROUND: Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. METHODS: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. RESULTS: The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. CONCLUSION: Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Línea Celular Tumoral , Transducción de Señal , Apoptosis , Neoplasias Encefálicas/patología , Proliferación CelularRESUMEN
BACKGROUND: After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking. METHODS: Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism. RESULTS: Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3ß activity, leading to ß-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and ß-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth. CONCLUSIONS: Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with ß-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Dopamina/uso terapéutico , Tirosina 3-Monooxigenasa/uso terapéutico , beta Catenina , Retroalimentación , Línea Celular Tumoral , Neoplasias Encefálicas/patología , Proliferación Celular , Receptores de Dopamina D2/uso terapéuticoRESUMEN
Although the chemo- and immuno-therapies have obtained good responses for several solid tumors, including those with brain metastasis, their clinical efficacy in glioblastoma (GBM) is disappointing. The lack of safe and effective delivery systems across the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (TME) are two main hurdles for GBM therapy. Herein, a Trojan-horse-like nanoparticle system is designed, which encapsulates biocompatible PLGA-coated temozolomide (TMZ) and IL-15 nanoparticles (NPs) with cRGD-decorated NK cell membrane (R-NKm@NP), to elicit the immunostimulatory TME for GBM chemo-immunotherapy. Taking advantage of the outer NK cell membrane cooperating with cRGD, the R-NKm@NPs effectively traversed across the BBB and targeted GBM. In addition, the R-NKm@NPs exhibited good antitumor ability and prolonged the median survival of GBM-bearing mice. Notably, after R-NKm@NPs treatment, the locally released TMZ and IL-15 synergistically stimulated the proliferation and activation of NK cells, leading to the maturation of dendritic cells and infiltration of CD8+ cytotoxic T cells, eliciting an immunostimulatory TME. Lastly, the R-NKm@NPs not only effectively prolonged the metabolic cycling time of the drugs in vivo, but also has no noticeable side effects. This study may offer valuable insights for developing biomimetic nanoparticles to potentiate GBM chemo- and immuno-therapies in the future.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Ratones , Animales , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Interleucina-15/uso terapéutico , Microambiente Tumoral , Biomimética , Línea Celular Tumoral , Temozolomida/uso terapéutico , Inmunoterapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patologíaRESUMEN
Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB.
RESUMEN
The standard regimen treatment has improved GBM outcomes, but the survival rate of patients is still unsatisfactory. Temozolomide (TMZ) resistance is one of main reasons limiting the therapeutic efficacy of GBM. However, there are currently no TMZ-sensitizing drugs available in the clinic. Here we aimed to study whether the antidiabetic drug Sitagliptin can inhibit the survival, stemness and autophagy of GBM cells, and thus enhance TMZ cytotoxicity. We used CCK-8, EdU, colony formation, TUNEL and flow cytometry assays to assess cell proliferation and apoptosis; sphere formation and limiting dilution assays to measure self-renewal and stemness of glioma stem cells (GSCs); Western blot, qRT-PCR or immunohistochemical analysis to measure the expression of proliferation or stem cell markers; Western blot/fluorescent analysis of LC3 and other molecules to evaluate autophagy formation and degradation in glioma cells. We found that Sitagliptin inhibited proliferation and induced apoptosis in GBM cells and suppressed self-renewal and stemness of GSCs. The in vitro findings were further confirmed in glioma intracranial xenograft models. Sitagliptin administration prolonged the survival time of tumor-bearing mice. Sitagliptin could inhibit TMZ-induced protective autophagy and enhance the cytotoxicity of TMZ in glioma cells. In addition, Sitagliptin acted as a dipeptidyl peptidase 4 inhibitor in glioma as well as in diabetes, but it did not affect the blood glucose level and body weight of mice. These findings suggest that Sitagliptin with established pharmacologic and safety profiles could be repurposed as an antiglioma drug to overcome TMZ resistance, providing a new option for GBM therapy.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animales , Ratones , Temozolomida , Fosfato de Sitagliptina/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Apoptosis , Autofagia , Glioblastoma/tratamiento farmacológico , Resistencia a Antineoplásicos , Antineoplásicos Alquilantes/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials.
RESUMEN
Aerobic glycolysis is the primary energy supply mode for glioblastoma (GBM) cells to maintain growth and proliferation. However, due to the metabolic reprogramming of tumor cells, GBM can still produce energy through fatty acid oxidation (FAO) and amino acid metabolism after blocking this metabolic pathway. In addition, GBM can provide a steady stream of nutrients through high-density neovascularization, which puts the block energy metabolism therapy for glioma in the situation of "internal and external problems". Herein, based on the abundant reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment and cytoplasm, we successfully designed and developed a cascade-responsive 2-DG nanocapsule delivery system. This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody (aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker (aV-siCPT1C). The surface of this nanocapsule (2-DG/aV-siCPT1C NC) is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1, which is highly expressed on the blood-brain barrier (BBB) and GBM cells, to effectively penetrate the BBB and target GBM. The nanocapsule realizes multidrug codelivery, jointly blocks glycolysis and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves the problems of low delivery efficiency of mAb in the central nervous system (CNS) and easy degradation of siRNA. In general, this drug joint delivery strategy could open up a new avenue for the treatment of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanocápsulas , Humanos , Glioblastoma/tratamiento farmacológico , Nanocápsulas/uso terapéutico , Línea Celular Tumoral , Metabolismo Energético , ARN Interferente Pequeño/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Microambiente TumoralRESUMEN
Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.
Asunto(s)
Neoplasias Encefálicas , Glioma , Animales , Temozolomida/farmacología , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , ARN Interferente Pequeño/farmacología , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/genética , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/farmacología , Antineoplásicos Alquilantes/farmacología , Resistencia a Antineoplásicos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genéticaRESUMEN
OBJECTIVE: To evaluate the value of texture analysis of routine MRI image in peritumoral edema of differentiating diagnosis between glioblastoma (GBM) and primary brain lymphoma (PBL). METHODS: The MRI imaging data of 22 patients with glioblastoma and 21 patients with PBL who were hospitalized in our hospital from January 2010 to October 2018 were selected. All the patients were pathologically diagnosed as glioblastoma or PBL, and MRI plain scan and enhanced examination were performed before operation. FireVoxel software was used to delineate the region of interest (ROI) on the most obvious level of peritumoral edema based on T1WI enhancement. Texture parameters were extracted and compared between glioblastoma and PBL. RESULTS: In the glioblastoma group, the inhomogeneity, kurtosis and entropy texture parameters were statistically different from those in the PBL group. The entropy parameter area under the curve (AUC) (0.903) was significantly better than the kurtosis parameter AUC (0.859) and the inhomogeneity parameter AUC (0.729). When the entropy parameter Cut-off point = 3.883, the sensitivity, specificity and accuracy of glioblastoma and PBL were 85.7, 86.4 and 86.0%, respectively, by differential diagnosis. CONCLUSION: Texture analysis of tumor peritumoral edema provided quantifiable information, which might be a new method for differentiating glioblastoma from PBL.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Linfoma , Humanos , Glioblastoma/diagnóstico por imagen , Glioblastoma/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Linfoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Diagnóstico Diferencial , Edema/diagnóstico , Encéfalo/patología , Estudios RetrospectivosRESUMEN
The metabolism of tumor cells is characterized by the regulation of demand, nutrient supply and metabolic enzymes, which are different in cancer tissues from those in corresponding healthy tissues. There is growing evidence that dietary composition influences biological processes that contribute to tumor incidence and progression as much as genetic status. One possibility for specific dietary interventions in cancer patients is to limit methionine intake. The role of methionine metabolism in tumors suggests that interference with the methionine metabolism network by either drug or environmental effects may show substantial therapeutic effects, but the molecular mechanism is not completely clear. In this study, methionine deprivation was found to downregulate cathepsin L (CTSL) and induce proliferation inhibition in glioma cells. We also demonstrated that CTSL is a tumor-related gene, and promotes the proliferation and invasion of glioma. Our results showed that the treatment of methionine metabolism and CTSL related genes in glioma cells may be a novel strategy for glioma therapy in the future.
RESUMEN
SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain-blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment.
RESUMEN
Bacterial infection is one of the most serious physiological conditions threatening human health. There is an increasing demand for more effective bacterial diagnosis and treatment through non-invasive approaches. Among current antibacterial strategies of non-invasive approaches, photothermal antibacterial therapy (PTAT) has pronounced advantages with properties of minor damage to normal tissue and little chance to trigger antimicrobial resistance. Therefore, we developed a fast and simple strategy that integrated the sensitive detection and photothermal therapy of bacteria by measuring adenosine triphosphate (ATP) bioluminescence following targeted photothermal lysis. First, 3-azido-d-alanine (d-AzAla) is selectively integrated into the cell walls of bacteria, photosensitizer dibenzocyclooctyne, and double sulfonic acid-modified indocyanine green (sulfo-DBCO-ICG) are subsequently designed to react with the modified bacteria through in vivo click chemistry. Next, the sulfo-DBCO-ICG modified bacteria under irradiation of 808 nm near-infrared laser was immediately detected by ATP bioluminescence following targeted photothermal lysis and even the number of bacteria on the infected tissue can be significantly reduced through PTAT. This method has demonstrated the ability to detect the presence of the bacteria for ATP value in 32 clinical samples. As a result, the ATP value over of 100 confirmed the presence of bacteria in clinical samples for 22 patients undergoing craniotomy and ten otitis media patients. Overall, this study paves a brand new avenue to facile diagnosis and a treatment platform for clinical bacterial infections.