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1.
Cancer Discov ; 9(10): 1340-1342, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31575562

RESUMO

Effective options are limited for patients with small-cell lung cancer who develop progressive disease during or after etoposide plus platinum-based therapy. In this issue of Cancer Discovery, Farago and colleagues highlight the data for temozolomide plus olaparib in this patient population and demonstrate the potential to accelerate biomarker discovery through co-clinical trials utilizing patient-derived xenografts.See related article by Farago et al., p. 1372.


Assuntos
Neoplasias Pulmonares , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Biomarcadores , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Recidiva Local de Neoplasia , Ftalazinas , Piperazinas , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 39(8): 4463-4465, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366545

RESUMO

This case report describes a patient with a rare occurrence of primary spinal intramedullary Ewing's sarcoma (ES) in the cervical and thoracic spine. The older age of disease occurrence, uncommon location in the cervical and thoracic spine, and EWSR1 gene fusion as the basis of diagnosis are unique features of this case. There is no clear protocol for treatment of primary extraskeletal ES of the spine, with controversy between evidence for pursuing surgery versus a combination of radiation and chemotherapy. Our patient was treated with temozolomide chemotherapy for recurrent metastatic disease of primary ES of the spine.


Assuntos
Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/tratamento farmacológico , Temozolomida/administração & dosagem , Adulto , Idoso , Humanos , Masculino , Pescoço/patologia , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/patologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/patologia , Parede Torácica/efeitos dos fármacos , Parede Torácica/patologia
3.
AAPS PharmSciTech ; 20(7): 259, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332574

RESUMO

The local delivery of chemotherapy drugs using implantable drug delivery systems is a promising strategy to the treatment of malignant brain tumors. In this study, core/shell chitosan-poly ethylene oxide-carbon quantum dots/carboxymethyl cellulose-polyvinyl alcohol (CS-PEO-CQDs/CMC-PVA) nanofibers were successfully prepared through coaxial electrospinning as a biodegradable polymeric implant for the local delivery of temozolomide (TMZ). Fluorescent carbon dots with carboxyl-rich surface were used as a trackable drug delivery agent for the localized cancer treatment. The effects of several preparation parameters such as voltage, shell to core flow rate, CS/PEO ratio, and PVA/CMC ratio on the structure of nanofibers were investigated. The best nanofibers were obtained in the condition of CS/PEO ratio of 80:20, CMC/PVA ratio of 20:80, shell to core flow rate of 3, and voltage of 25 V. SEM images showed that such nanofibers possess a smooth surface and bead-less structures. The results obtained by DSC indicated that TMZ trapped in the nanofibers existed in an amorphous or disordered crystalline status. In vitro release profile of TMZ from core-shell nanofibers had biphasic patterns. After an initial burst, a continuous drug release was observed for up to 28 days. The in vitro antitumor activity of CQDs-TMZ was tested against the tumor U251 cell lines than the free drug. It has been found that the cytotoxicity of TMZ to U251 cancer cells is enhanced when TMZ is conjugated with CQDs.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Nanofibras/química , Pontos Quânticos/química , Temozolomida/administração & dosagem , Antineoplásicos Alquilantes/química , Carboximetilcelulose Sódica/química , Linhagem Celular Tumoral , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Humanos , Polietilenoglicóis/química , Álcool de Polivinil/química , Temozolomida/química
4.
J Biomed Nanotechnol ; 15(7): 1468-1481, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31196351

RESUMO

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, temozolomide (TMZ) is widely used for the treatment of GBM, but the effects of TMZ for GBM are limited by the presence of rapid resistance. It was reported that a small percentage of glioma cells which called glioma stem cells (GSCs) lead GBM resistance to TMZ, and sensitizes GSCs to TMZ was an effective way to solve the TMZ resistance and cure the GBM. A polypeptide αCT1 is selective inhibitor of connexin43 (Cx43) channels which can sensitizes GSCs to TMZ. However, in clinical, the biodegradation of peptides and non-targeting greatly affect the efficacy of polypeptide. Magnetic mesoporous silica nanoparticles (MMSNs) is a very effective peptide drug carrier in which peptides were loaded into its porous structure prevent protease degradation and the drugs can be concentrated in the tumor area without diffusion within a magnetic field. CD133 was a cell marker of GSCs which CD133 can be used in target treatment of GSCs. In this study, we aim to treat TMZ resistant gliomas. The αCT1 and CD133 antibody were first loaded on the MMSNs to construct a target MMSNs drug carrier, the MMSNs constructed here have good biocompatibility, drug loading capacity and release properties. The drug nano-carriers prepared here can enter the GSCs through endocytosis effectively, the results indicated that the combination of MMSNs@ αCT1@AbCD133 and TMZ can block the protein kinase B (AKT)/AMP-activated protein kinase (AMPK)/AMP-activated protein kinase (MTOR) signaling pathway of GSCs and then induce autophagy, apoptosis and the death of GSCs, MMSNs@ αCT1@AbCD133 and TMZ combination also can inhibit the growth of solid tumor. In short, this study indicated that MMSNs@ αCT1@AbCD133 prepared here can sensitizes GSCs to TMZ, combination of MMSNs@ αCT1@AbCD133 and TMZ can be used in treatment of GSCs, we hoped that this study can provide a new way for eradication treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Linhagem Celular Tumoral , Dacarbazina , Humanos , Células-Tronco Neoplásicas , Dióxido de Silício , Temozolomida
5.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
6.
Neurologist ; 24(3): 87-89, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045718

RESUMO

Pilocytic astrocytomas (PA) are highly vascular tumors with vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor-2 (VEGFR-2) signaling present in the tumor vasculature. PA may, therefore, be responsive to VEGF blockade with bevacizumab (BEV). Data regarding the use of BEV in refractory PA in adults are limited primarily to case reports and case series of patients with recurrent PA. We conducted a single-center, retrospective cohort study from 2009 to 2018. We screened 426 patients with pathologically confirmed PA. We identified 5 adult patients with PA who received BEV at our institution with sufficient clinical follow-up to derive evidence of the efficacy and toxicity. All 5 patients experienced tumor progression after initial therapies which included surgery, radiation, and chemotherapy. Four patients received BEV as monotherapy, whereas 1 received BEV with the continuation of previously initiated alkylating chemotherapy (temozolomide). The average duration of BEV therapy was 10.2 months (range, 1 to 20 mo) with an average follow-up of 47 months (range, 6 to 112 mo). One patient had a severe necrotizing rash in areas of skin contact and discontinued after 1 cycle of BEV. All patients had stabilization per RANO criteria, with 1 patient experiencing progression after 10 months on treatment. One patient had disease progression 5 years after completion of BEV, but the tumor responded to repeat treatment with BEV. Our institution's experience with the use of BEV in recurrent PA is in line with previous reports of therapeutic benefit in recurrent adult PA.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Bevacizumab/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Estudos Retrospectivos , Temozolomida/uso terapêutico , Resultado do Tratamento , Adulto Jovem
7.
Mol Med Rep ; 19(6): 5301-5308, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059108

RESUMO

Temozolomide (TMZ) is widely used as a chemotherapeutic agent in the treatment of glioma; however, the development of drug resistance remains a major obstacle in the effective treatment of glioblastoma. Increasing evidence has indicated that microRNAs (miRs) are involved in the drug resistance of glioma; however, the role of miR­186­5p in the TMZ resistance of glioblastoma remains unknown. In the present study, the role of miR­186­5p in the resistance of glioblastoma to TMZ was investigated. mRNA and protein expression levels were detected via reverse transcription­quantitative PCR and western blot analysis, respectively. It was determined that miR­186­5p was significantly downregulated in glioblastoma tissues and cell lines. Additionally, the expression of miR­186­5p was decreased, whereas that of Twist1 was upregulated during the development of drug resistance in glioma cells. The introduction of miR­186 into glioblastoma cells via transfection decreased the proliferation and TMZ resistance of glioblastoma cells, as determined via 5­ethynyl­2'­deoxyuridine and Cell Counting Kit­8 assays, whereas the inhibition of miR­186­5p induced opposing effects. Furthermore, luciferase reporter and expression rescue assays revealed that miR­186­5p bound to the 3'­untranslated region of Twist­related protein 1 (Twist1). In conclusion, the present study demonstrated that downregulation of miR­186­5p may contribute to the proliferation and drug resistance of glioblastoma cells via the regulation of Twist1 expression. These results suggested that miR­186­5p may be a novel therapeutic target in the treatment of glioblastoma.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Regiões 3' não Traduzidas , Adulto , Idoso , Antagomirs/metabolismo , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Glioblastoma/metabolismo , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Temozolomida/farmacologia , Proteína 1 Relacionada a Twist/antagonistas & inibidores , Proteína 1 Relacionada a Twist/genética
8.
Int J Oncol ; 54(6): 2189-2199, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081046

RESUMO

Glioblastoma (GB) is the most common and aggressive malignant tumor of the central nervous system. Despite current intensive treatment regimens, consisting of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy, the prognosis of patients with GB remains extremely poor. Considering that alterations of the p53 tumor suppressor pathway have a key role in both GB development and resistance to TMZ treatment, the re­activation of p53 could be an effective therapeutic approach against GB. In this study, we challenged p53 wild­type and mutant GB cell lines with RITA, a molecule originally identified for its ability to restore p53 functions, although it was subsequently shown to act also through p53­independent mechanisms. We examined the effects of RITA on GB cell viability, through MTS and clonogenic assays, and analyzed cell death through cytoflourimetric analyses. In all the tested GB cell lines, RITA significantly reduced the cell proliferative and clonogenic potential and induced cell accumulation in the S and/or G2/M cell cycle phases and massive p53­dependent apoptosis. Moreover, RITA was more effective than the well­known p53 re­activating molecule, nutlin­3, and did not affect the viability of normal astrocytes. In addition, RITA decreased survivin expression and induced DNA damage, two mechanisms that likely contribute to its anti­tumor effects. Furthermore, RITA synergized with TMZ and was able to decrease the expression of MGMT, which is a crucial player in TMZ resistance. Thus, although further studies are warranted to clarify the exact mechanisms of action of RITA, the data of this study suggest the potential of such an approach for GB therapy, which may also help to overcome resistance to TMZ.


Assuntos
Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Glioblastoma/metabolismo , Temozolomida/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Imidazóis/farmacologia , Mutação , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética
9.
Nat Commun ; 10(1): 2045, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053733

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , RNA Longo não Codificante/metabolismo , Temozolomida/farmacologia , Adulto , Animais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Análise de Sobrevida , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Am J Chin Med ; 47(3): 657-674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974966

RESUMO

Glioblastoma (GBM) is the most commonly occurring tumor in the cerebral hemispheres. Currently, temozolomide (TMZ), an alkylating agent that induces DNA strand breaks, is considered the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. We have recently established and characterized TMZ-resistant human glioma cells. The aim of this study is to investigate whether curcumin modulates cell apoptosis through the alternation of the connexin 43 (Cx43) protein level in TMZ-resistant GBM. Overexpression of Cx43, but not ATP-binding cassette transporters (ABC transporters), was observed (approximately 2.2-fold) in TMZ-resistant GBM cells compared to the Cx43 levels in parental GBM cells. Furthermore, at a concentration of 10 µ M, curcumin significantly reduced Cx43 protein expression by about 40%. In addition, curcumin did not affect the expression of other connexins like Cx26 or epithelial-to-mesenchymal transition (EMT) proteins such as ß -catenin or α E-catenin. Curcumin treatment led to an increase in TMZ-induced cell apoptosis from 4% to 8%. Importantly, it did not affect the mRNA expression level of Cx43. Concomitant treatment with the translation inhibitor cycloheximide (CHX) exerted additional effects on Cx43 degradation. Treatment with the autophagy inhibitor 3-MA (methyladenine) did not affect the curcumin-induced Cx43 degradation. Interestingly, treatment with the proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) significantly negated the curcumin-induced Cx43 degradation, which suggests that curcumin-induced Cx43 degradation occurs through the ubiquitin-proteasome pathway.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Conexina 43/metabolismo , Curcumina/farmacologia , Glioblastoma/genética , Glioblastoma/patologia , Proteólise/efeitos dos fármacos , Temozolomida/farmacologia , Humanos , Estimulação Química , Células Tumorais Cultivadas
11.
Life Sci ; 226: 98-106, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980849

RESUMO

AIMS: The acquired drug resistance has been regarded as a main barrier for the effective treatment of temozolomide (TMZ) in glioblastoma (GBM). MiR-126-3p is commonly down-regulated and exerts tumor-suppressive roles in kinds of human cancers, including GBM. This study was designed to investigate the functions and mechanisms of miR-126-3p in regulating TMZ resistance in GBM. MATERIALS AND METHODS: qRT-PCR analysis was used to measure the expressions of miR-126-3p and SOX2 mRNA in GBM tissues and cells. Cell viability, colony forming ability and apoptosis were detected to evaluate the effect of miR-126-3p or SOX2 on TMZ resistance. Luciferase reporter experiments were applied to identify the target genes of miR-126-3p. Western blot analysis was performed to determine the protein levels associated with Wnt/ß-catenin signaling. TOP/FOP Flash assays were conducted to determine the effects of miR-126-3p or SOX2 on Wnt/ß-catenin signaling. KEY FINDINGS: miR-126-3p expression was decreased in TMZ-resistant GBM tissues and cells. High levels of miR-126-3p enhanced TMZ sensitivity by inhibiting cell viability, reducing colony forming potential and inducing apoptosis. Additionally, SOX2 was identified as a downstream target of miR-126-3p. On the contrary, SOX2 overexpression conferred TMZ resistance of GBM cells. Moreover, miR-126-3p-mediated TMZ sensitivity was reversed following increased expression of SOX2. Furthermore, miR-126-3p-induced inactivation of Wnt/ß-catenin signaling was greatly abrogated by SOX2 up-regulation. SIGNIFICANCE: MiR-126-3p sensitizes GBM cells to TMZ possibly by repressing SOX2 expression and blocking Wnt/ß-catenin signaling. This study provides novel targets to overcome TMZ resistance in GBM chemotherapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Temozolomida/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Antineoplásicos Alquilantes/farmacologia , Apoptose/fisiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Fatores de Transcrição SOXB1/biossíntese , Fatores de Transcrição SOXB1/genética
12.
Anticancer Res ; 39(4): 2043-2051, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952748

RESUMO

BACKGROUND/AIM: The need for more effective treatment modalities that can improve the clinical outcome of patients with glioblastoma multiforme remains imperative. Dendritic cell vaccination is a fast-developing treatment modality, currently under exploration. Functional immune cell subpopulations may play a role in the final outcome. MATERIALS AND METHODS: Data from 101 patients drawn from the HGG-2010 trial, including baseline patient characteristics and fluorescence-activated cell sorting of immune cell subpopulations, were analyzed by statistical and machine-learning methods. RESULTS: The analysis revealed strong correlations between immune profiles and overall survival, when the extent of resection and the vaccination schedule were used as stratification variables. CONCLUSION: A systematic, in silico workflow detecting strong and statistically significant correlations between overall survival and immune profile-derived quantities obtained at the start of dendritic cell vaccination was devised. The derived correlations could serve as a basis for the identification of prognostic markers discriminating between potential long- and short-term survivors of patients with glioblastoma multiforme.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Células Dendríticas/imunologia , Glioblastoma/imunologia , Glioblastoma/terapia , Temozolomida/uso terapêutico , Adulto , Idoso , Terapia Combinada , Feminino , Citometria de Fluxo , Humanos , Imunoterapia , Leucaférese , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento , Vacinação
13.
Nat Commun ; 10(1): 1787, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992437

RESUMO

The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/genética , Plasticidade Celular/efeitos dos fármacos , Glioblastoma/genética , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/uso terapêutico , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Plasticidade Celular/genética , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Cancer Res Clin Oncol ; 145(6): 1495-1507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028540

RESUMO

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Aprepitanto/administração & dosagem , Aprepitanto/farmacologia , Auranofina/administração & dosagem , Auranofina/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Captopril/administração & dosagem , Captopril/farmacologia , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Camundongos , Camundongos SCID , Minociclina/administração & dosagem , Minociclina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Sertralina/administração & dosagem , Sertralina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Clin Nucl Med ; 44(5): e329-e335, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932975

RESUMO

PURPOSE: Combinations of therapies may enhance therapeutic effects without significantly increasing the incidence of adverse events. However, there are few data regarding survival after concomitant chemotherapy and peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-octreotate in patients with neuroendocrine tumors (NETs). Thus, we explored the outcome of this combination of therapies. METHODS: Fifteen patients with somatostatin receptor-positive, rapidly progressive G2/G3 NETs during chemotherapy or PRRT alone from 2 German cancer centers were included in the retrospective analysis. The patients received a combination of PRRT and chemotherapy with temozolomide (n = 3) or temozolomide plus capecitabine (n = 12). To evaluate the effects of the combined treatment, we assessed the responses, survival, and adverse events. RESULTS: The cumulative administered activity of [Lu]Lu-octreotate had a median of 21.3 GBq after 3 cycles of combination therapy. The patients exhibited a median progression-free survival of 7.1 months and a median overall survival of 25.3 months. The clinical benefit (objective response and stable disease) rates were as follows: 55% of patients according to CT, 38% in [F]F-FDG PET/CT, and 44% in [Ga]Ga-DOTATOC PET/CT. One patient with rapidly progressing liver metastases experienced grade 4 liver failure according to the Common Terminology Criteria for Adverse Events (version 5.0). Four other patients (27%) experienced significantly elevated (grade 3) liver parameters. CONCLUSIONS: According to different imaging modalities, the combination of PRRT and temozolomide +/- capecitabine led to disease control in 38% to 55% of the progressive NETs after PRRT or chemotherapy alone failed. The overall survival in this extensively pretreated group of patients was nearly 25 months. The majority of patients did not experience any serious adverse events.


Assuntos
Quimiorradioterapia/métodos , Tumores Neuroendócrinos/terapia , Octreotida/análogos & derivados , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico
16.
J Clin Neurosci ; 64: 18-21, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948314

RESUMO

Survival outcomes for patients with glioblastoma (GBM) are universally poor with only a small percentage of patients surviving five years beyond initial diagnosis. Activation of the immune system against tumor cells is the basis of immunotherapy and aims to facilitate long-term immune surveillance and tumor suppression. Cytomegalovirus (CMV) has emerged as an immunologic target in GBM given that tumor cells have been shown to express the CMV-associated proteins IE1 and pp65. Moreover, vaccine therapy targeting CMV antigens has promoted improved survival outcomes with long-term survivors. In this report, we present the case of a 69 year-old woman with GBM who survived seven years post-diagnosis. Following tumor resection, the patient underwent concomitant radiation and temozolomide therapy that was complicated by CMV colitis and abdominal abscesses. Despite not receiving adjuvant temozolomide, the patient demonstrated a five year progression-free survival before requiring re-resection for radiation necrosis. Following re-resection, the patient survived for two additional years. As the patient's tumor stained positive for CMV antigens IE1 and pp65, it is hypothesized that she developed an immune response against CMV during recovery that contributed to anti-tumor surveillance and prolonged survival. Overall, this case supports further investigation into the role of CMV and immunotherapy in GBM.


Assuntos
Neoplasias Encefálicas/imunologia , Colite/virologia , Infecções por Citomegalovirus/imunologia , Glioblastoma/imunologia , Hospedeiro Imunocomprometido , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/virologia , Quimiorradioterapia/métodos , Colite/complicações , Feminino , Glioblastoma/patologia , Glioblastoma/virologia , Humanos , Proteínas Imediatamente Precoces/imunologia , Fosfoproteínas/imunologia , Temozolomida/uso terapêutico , Proteínas da Matriz Viral/imunologia , Ativação Viral/imunologia
17.
J Nanobiotechnology ; 17(1): 47, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935403

RESUMO

BACKGROUND: Glioma is a common brain tumor with a high mortality rate. A small population of cells expressing stem-like cell markers in glioma contributes to drug resistance and tumor recurrence. METHODS: Porous silicon nanoparticles (PSi NPs) as photothermal therapy (PTT) agents loaded with TMZ (TMZ/PSi NPs), was combined with hyperbaric oxygen (HBO) therapy in vitro and in vivo. To further investigate underlying mechanism, we detected the expression of stem-like cell markers and hypoxia related molecules in vitro and in vivo after treatment of TMZ/PSi NPs in combination with PTT and HBO. RESULTS: NCH-421K and C6 cells were more sensitive to the combination treatment. Moreover, the expression of stem-like cell markers and hypoxia related molecules were decreased after combination treatment. The in vivo results were in line with in vitro. The combination treatment presents significant antitumor effects in mice bearing C6 tumor compared with the treatment of TMZ, PTT or TMZ/PSi NPs only. CONCLUSION: These results suggested the TMZ/PSi NPs combined with HBO and PTT could be a potential therapeutic strategy for glioma.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/terapia , Glioma/terapia , Nanopartículas/química , Células-Tronco Neoplásicas/patologia , Silício/química , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/química , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Glioma/patologia , Humanos , Oxigenação Hiperbárica , Hipertermia Induzida , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Tamanho da Partícula , Porosidade , Ratos , Temozolomida/química
18.
J Exp Clin Cancer Res ; 38(1): 166, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992025

RESUMO

BACKGROUND: Acquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes. METHOD: LncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1. RESULT: It was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients. CONCLUSION: We can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.


Assuntos
Proteínas de Ligação a DNA/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/sangue , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
19.
Phytother Res ; 33(6): 1736-1747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31006910

RESUMO

Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene-type sesquiterpene isolated from the rhizomes of Rhizoma curcumae, exhibited a potential cytotoxic effect on temozolomide (TMZ)-resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4-Akt-ERK signalling, inflammatory responses, and cytokine levels but activated caspase-dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual-luciferase reporter assay revealed that inhibition of EGR1-mediated transcription might have contributed to the FUR-dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR-induced CSPG4 inhibition and the suppression of EGR1-dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1-dependent negative feedback loop of the CSPG4 pathway during FUR-induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Furanos/farmacologia , Glioblastoma/tratamento farmacológico , Sesquiterpenos/farmacologia , Temozolomida/uso terapêutico , Adulto , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Temozolomida/administração & dosagem , Transcrição Genética/efeitos dos fármacos
20.
Oxid Med Cell Longev ; 2019: 3061607, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984333

RESUMO

The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Ubiquinona/análogos & derivados , Animais , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Ratos Wistar , Temozolomida/farmacologia , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
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