Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the...Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.展开更多
Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which ...Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.展开更多
Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to...Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.展开更多
Objective:Temozolomide(TMZ)is commonly used for glioblastoma multiforme(GBM)chemotherapy.However,drug resistance limits its therapeutic effect in GBM treatment.RNA-binding proteins(RBPs)have vital roles in posttranscr...Objective:Temozolomide(TMZ)is commonly used for glioblastoma multiforme(GBM)chemotherapy.However,drug resistance limits its therapeutic effect in GBM treatment.RNA-binding proteins(RBPs)have vital roles in posttranscriptional events.While disturbance of RBP-RNA network activity is potentially associated with cancer development,the precise mechanisms are not fully known.The SNRPG gene,encoding small nuclear ribonucleoprotein polypeptide G,was recently found to be related to cancer incidence,but its exact function has yet to be elucidated.Methods:SNRPG knockdown was achieved via short hairpin RNAs.Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG.Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues.Results:The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53.In addition,the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent.Furthermore,SNRPG was increased in TMZ-resistant GBM cells,and downregulation of SNRPG potentially sensitized resistant cells to TMZ,suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.Our data confirmed that SNRPG suppression sensitizes GBM cells to TMZ by targeting Myc via the p53 signaling cascade.Conclusions:These results indicated that SNRPG is a probable molecular target of GBM and suggested that suppressing SNRPG in resistant GBM cells might be a substantially beneficial method for overcoming essential drug resistance.展开更多
Objective To investigate the function of primary cilia in regulating the cellular response to temozolomide(TMZ)and ionizing radiation(IR)in glioblastoma(GBM).Methods GBM cells were treated with TMZ or X-ray/carbon ion...Objective To investigate the function of primary cilia in regulating the cellular response to temozolomide(TMZ)and ionizing radiation(IR)in glioblastoma(GBM).Methods GBM cells were treated with TMZ or X-ray/carbon ion.The primary cilia were examined by immunostaining with Arl13 b andγ-tubulin,and the cellular resistance ability was measured by cell viability assay or survival fraction assay.Combining with cilia ablation by IFT88 depletion or chloral hydrate and induction by lithium chloride,the autophagy was measured by acridine orange staining assay.The DNA damage repair ability was estimated by the kinetic curve ofγH2 AX foci,and the DNAdependent protein kinase(DNA-PK)activation was detected by immunostaining assay.Results Primary cilia were frequently preserved in GBM,and the induction of ciliogenesis decreased cell proliferation.TMZ and IR promoted ciliogenesis in dose-and time-dependent manners,and the suppression of ciliogenesis significantly enhanced the cellular sensitivity to TMZ and IR.The inhibition of ciliogenesis elevated the lethal effects of TMZ and IR via the impairment of autophagy and DNA damage repair.The interference of ciliogenesis reduced DNA-PK activation,and the knockdown of DNA-PK led to cilium formation and elongation.Conclusion Primary cilia play a vital role in regulating the cellular sensitivity to TMZ and IR in GBM cells through mediating autophagy and DNA damage repair.展开更多
High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemot...High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemotherapy. Alkylating agent temozolomide has been established as the standard chemotherapy while its resistance inevitable during treatment. This phenomenon seriously influences the prognosis of patients suffering from high grade gliomas. This review aims to elucidate temozolomide chemoresistance mechanisms through three chapters including O^6-methylguanine-DNA methyltransferase(MGMT) methylation, mismatch repair mutation and epigenetic regulation consisting of p21, chromatin and histone, Y-box binding protein-1 and micro RNAs.展开更多
BACKGROUND Neuroendocrine carcinoma of the breast(NECB)is a rare type of malignant tumor.Due to the rarity of NECB,the relevant literature mostly comprises case reports.Available data on treatment options for NECB are...BACKGROUND Neuroendocrine carcinoma of the breast(NECB)is a rare type of malignant tumor.Due to the rarity of NECB,the relevant literature mostly comprises case reports.Available data on treatment options for NECB are very limited.CASE SUMMARY A 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography(CT)imaging.She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital.The patient initially presented with a painful lesion of the right breast.She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy.She was regularly followed every 3 mo after surgery.Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm×6.3 cm.Chest CT revealed masses in the anterior chest wall and lung.Core needle biopsy of the lesion revealed liver metastases of NECB.A bone scan showed right second anterior rib metastases.Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor.She stopped receiving endocrine therapy and then received etoposide and cisplatin(EP)chemotherapy as a firstline treatment regimen for six cycles at our hospital after liver,bone,and lung metastases.On October 2017,the chemotherapy regimen was changed to S-1(40mg twice daily,days 1-14)combined with temozolomide(200 mg once daily,days 10-14)(STEM)every 21 d as a second-line treatment regimen due to disease progression.Progression-free survival(PFS)and adverse effects after treatment were analyzed,and the efficacy of the STEM regimen was assessed using RECIST version 1.1.This patient achieved a partial response after using the STEM regimen,with a PFS of 23 mo.Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.CONCLUSION This case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB.STEM is still highly effective in patients who show disease progression with the EP regimen.More evidence is needed to prove the validity of STEM.展开更多
Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatm...Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.展开更多
Objective: To investigate the role of adiponectin in human glioma cell lines against the temozolomide and the molecular regulation mechanism. Methods: Human glioma cell lines U251 and U-87MG were cultured in Dulbecco...Objective: To investigate the role of adiponectin in human glioma cell lines against the temozolomide and the molecular regulation mechanism. Methods: Human glioma cell lines U251 and U-87MG were cultured in Dulbecco’s modified eagle medium (DMEM) containing 4500 mg/L glucose. MTT was used to measure cell growth ratio. Western blot was used to detect the protein levels of autophagy-related protein (Beclin 1, LC3 I/II, p62) and phosphorylated AMPK (p-AMPK) in human glioma cell lines. After AICAR and Compound C were administered, the change of p-AMPK and the autophagy level were examined by western blot. Results: While adiponectin stimulates AMPK in phosphatase and up-regulates the level of autophagy, human glioma cell lines obtain more resistance against the temozolomide, which is facilitated by AICAR and weakened by Compound C. Conclusion: As an important adipokine, adiponectin can up-regulate the glioma cell autophagy by activating the AMPK signaling pathway which increases the resistance of glioma cells to temozolomide.展开更多
The multifocal glioblastomas (GBM) are tumors with multiple discrete areas of contrast enhancing tumors which have considerably poorer prognosis than solitary GBM. Median overall survival of diagnosed patients almost ...The multifocal glioblastomas (GBM) are tumors with multiple discrete areas of contrast enhancing tumors which have considerably poorer prognosis than solitary GBM. Median overall survival of diagnosed patients almost twice as less than solitary presentation. We present a case report of multifocal GBM. A 72-year old right-handed male was evaluated at the Neuro-Oncology Clinic of Baylor Scott and White Hospital (Central Division). Patient presented at this hospital because of persistent progressive headaches, confusion, and an incident of fall. Physical evaluation revealed neurological impairments. Brain magnetic resonance imaging (MRI) revealed heterogeneous contrast enhancing lesions with associated vasogenic oedema. Patient underwent a stereotactic biopsy analysis of the larger lesion and pathology evaluation concluded an isocitrate dehydrogenase 1 and 2 wild type GBM with unmethylated O-6-methylguanine- DNA methyltransferase. Treatment remedies: Patient received 4 weeks concurrent radiation therapy along with combination of temozolomide at dose of 75 mg/m^2 followed adjuvant temozolomide for 10 cycles with bevacizumab at 10 mg/kg every 2 weeks and Optune treatment. Post treatment evaluation: Repeat MRIs showed near complete resolution of the tumors at 26 months of treatment along with improvement of neurological status. Conclusion: Due to limitations of surgical manipulations in multifocal GBM diagnosed patients, combinational chemo and radiation therapy is the treatment of choice for most cases. Using additional novel treatment with non-invasive therapeutic device proven to be effective is another excellent approach to the established practice. Therefore, combination therapy of Optune plus temozolomide and bevacizumab might be a promising remedy for newly diagnosed multifocal glioblastomas.展开更多
[Objectives] To observe the clinical efficacy,adverse reaction and survival time of temozolomide combined with whole brain radiotherapy in the treatment of lung cancer. [Methods] A total of 43 patients with lung cance...[Objectives] To observe the clinical efficacy,adverse reaction and survival time of temozolomide combined with whole brain radiotherapy in the treatment of lung cancer. [Methods] A total of 43 patients with lung cancer and cerebral metastases were reviewed and analyzed. Three-dimensional conformal radiotherapy(3D-CRT) technique was used to perform whole brain radiotherapy,one time a day and5 times a week. At the same time of radiotherapy,temozolomide chemotherapy was performed,150 mg/( m2·d),continuous oral administration of 5 d,every 28 days were a cycle( those patients who continue receiving temozolomide chemotherapy did not receive other related antitumor therapy,such as systemic chemotherapy and molecular targeted therapy,etc.),and drugs were administered for 4-6 cycles according to tolerance of patients. Kaplan-Meier method was used to calculate the survival rate. [Results]The objective response rate of 43 patients was79. 0%(34/43),in which CR was 6/43,PR was 28/43,and 9 cases had PD. By December 31,2016,7 patients in 43 cases died,one patient died of cerebral hernia due to intracranial lesions and 6 patients died of failure of other important organs due to metastasis. The OS and PFS of the whole group of patients in one year were 49. 1% and 56. 9% respectively. The adverse reactions were mild and the patients could tolerate such treatment. [Conclusions] Temozolomide combined with whole brain radiotherapy in the treatment of lung cancer with cerebral metastases has excellent clinical efficacy,while patients can tolerate such treatment.展开更多
Objective:To investigate the expression level of long chain non coding RNAH19 in advanced gliomas and its relationship with glioma cell temozolomide (TMZ) resistance, and make a preliminary study on their related mech...Objective:To investigate the expression level of long chain non coding RNAH19 in advanced gliomas and its relationship with glioma cell temozolomide (TMZ) resistance, and make a preliminary study on their related mechanism.Methods:Tissue samples of normal brain tissue, early onset and recurrence of high grade gliomas were collected, and the expression of LNC H19 was detected by reverse transcription polymerase chain reaction (RT-PCR). The construction of Resistant U251 TMZ Resistant (U251-TR) Cell Lines were completed by intermittent concentration gradient increments and verified by MTT method. The changes in the expression of LncRNA H19 was detected by RT-PCR, lovirus transfection was used to construct U251-TR cell line with stable interference with LNC H19 (U251-TRsiLNC H19), and MTT assay was used to observe the changes of TMZ half-maximal inhibitory concentration (IC50). Western Blot and RT-PCR were used to detect the changes of O6-methylguanine DNA methyltransferase (MGMT) in U251, U251-TR and U251-TRsiLNC H19.Results: The results of RT-PCR showed that the expression of LNC H19 in high-grade glioma was significantly higher than that in primary glioma tissue and normal brain tissue. The IC50 value and drug resistance index of U251-TR cell line were significantly increased, the expression of LncRNA H19 in U251-TR cell line was significantly higher than that in U251 cells and the expression of MGMT were also increased. We succeeded in interfering with the expression of LNC H19 in the U251-TR cell line, and found that the IC50 value and drug resistance index of U251-TR cell line were decreased significantly and the expression of MGMT were also decreased.Conclusion:LNC H19 is highly expressed in recurrent high-grade gliomas, which may increase the level of MGMT, leading to the occurrence of glioma cell TMZ resistance. LNC H19 is a key factor in the occurrence of TMZ resistance in glioma cells.展开更多
Background and Aim: In this study, it was aimed to examine the cytotoxic effect of temozolomide (TMZ) treatment, on MCF-7 and SKBR3 cell lines, to study the methylation levels of MGMT gene expression and gene promoter...Background and Aim: In this study, it was aimed to examine the cytotoxic effect of temozolomide (TMZ) treatment, on MCF-7 and SKBR3 cell lines, to study the methylation levels of MGMT gene expression and gene promoter region. Methods: The MTT test was performed to determine the effective dose of TMZ. The time-dependent cell survival test was performed after the IC50 value was found. Western blotting was performed to determine MGMT gene expression levels. High Resolution Melting (HRM) technique was used to determine the methylation levels of MGMT gene promoter region. Results: TMZ has been shown to have a high cytotoxic effect on SKBR3 cell line and low cytotoxicity on MCF-7. When MGMT expression levels before and after TMZ treatment were observed by western blotting, the gene expression levels of TMZ treatment were shown to decrease in both cell lines. It was observed that MGMT gene promoter region was hypermethylated in two cell lines, and that the application of TMZ further increased the methylation levels in the promoter region. Conclusions: It was seen that TMZ could be used as a single agent in SKBR-3 cell line. With this study on breast cancer, it is expected that temozolomide treatment will lead future in vitro and in vivo studies for breast cancer.展开更多
Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods ...Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods A total of 40 patients with pathologically confirmed malignant gliomas were enrolled. All patients had pretreated with radiotherapy and had assessable lesions.展开更多
Objective To explore the effective treatment for refractory piuitary adenomas. Methods Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to temozolomide,we treated a refractory pituita...Objective To explore the effective treatment for refractory piuitary adenomas. Methods Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to temozolomide,we treated a refractory pituitary adenoma patient. Results MGMT expression in this case was at low level,and primary pituitary adenoma cells were sensitive to temozolomide in vitro. The tumor volume展开更多
Glioma is a common tumor originating in the brain that has a high mortality rate.Temozolomide(TMZ)is the first-line treatment for high-grade gliomas.However,a large pro-portion of gliomas are resistant to TMZ,posing a...Glioma is a common tumor originating in the brain that has a high mortality rate.Temozolomide(TMZ)is the first-line treatment for high-grade gliomas.However,a large pro-portion of gliomas are resistant to TMZ,posing a great challenge to their treatment.In the study,the specific functions and mechanism(s)by which cortistatin(CORT)regulates TMZ resis-tance and glioma progression were evaluated.The decreased expression of CoRT was detected in glioma tissues,and highly expressed CORT was associated with a better survival rate in pa-tients with glioma.CORT overexpression notably decreased the capacity of glioma cells to pro-liferate and migrate in vitro and to form tumors in vivo.CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT,p21,and Puma expression.Importantly,CORT overexpression reduced the resistance of gliomas to TMZ in vivo.CORT expression Was negatively correlated with MGMT expression in both glioma tissues and cells,and it was found that CORT inhibited NF-kB pathway activation in glioma cells,thereby inhibiting MGMT expression.In conclusion,CORT regulates glioma cell growth,migration,apoptosis,and TMZ resistance by weakening the activity of NF-kB/p65 and thereby regulating MGMT expression.The CORT/NF-kB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ.Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells,independent of its effects on TMZ resistance,providing evidence of novel therapeutic targets for glioma that should be evaluated infurther studies.展开更多
Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of...Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of O6-methylguanine methyltransferase(MGMT)and/or lack of a DNA repair pathway in GBM cells.Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics.However,the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared.This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines.It also summarizes potential treatment options for TMZ resistant GBMs.展开更多
Background:High-grade glioma(HGG)is a fatal human cancer.Bortezomib,a proteasome inhibitor,has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation.This study aimed to...Background:High-grade glioma(HGG)is a fatal human cancer.Bortezomib,a proteasome inhibitor,has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation.This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas.Methods:U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay,tumor cell spheroid growth,and colony formation assay.Cell apoptosis and cell cycle were detected by flow cytometry.Temozolomide(TMZ)-insensitive cell lines were induced by long-term TMZ treatment,and cells with stem cell characteristics were enriched with stem cell culture medium.The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction,and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections.Via inoculating U87 cells subcutaneously,glioma xenograft models in nude mice were established for drug experiments.Patient survival data were analyzed using the Kaplan-Meier method.Results:Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose-and time-dependent manner by inducing apoptosis and cell cycle arrest.Bortezomib also significantly inhibited the spheroid growth,colony formation,and stem-like cell proliferation of U251 and U87 cells.When administrated in combination,bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo.Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1(FOXM1)and its target gene Survivin.The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients.Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor progno-sis in glioma patients.Conclusions:Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy,probably via down-regulating the FOXM1-Survivin axis.Bortezomib might be a promising agent for treating malignant glioma,alone or in combination with TMZ.展开更多
Background:Adjuvant temozolomide(TMZ)chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma(HGG).However,the influence of long-term TMZ chemotherapy on serum ions concentrat...Background:Adjuvant temozolomide(TMZ)chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma(HGG).However,the influence of long-term TMZ chemotherapy on serum ions concentration is unclear.Methods:One hundred and thirty-eight patients with HGG were included.Their blood samples were collected for blood biochemistry and routine test.The alteration in serum ions concentration,total protein,albumin,globin,and blood cells counts were used to identify the impact of long-term TMZ chemotherapy.Results:Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles,we identified that serum potassium concentration had a downward trend after TMZ administration(1st vs.6th,p<0.001;1st vs.12th,p<0.001).Additionally,the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles(r=−0.649,p=0.023).The hematological adverse events mainly centered on grade 1 to 2.Conclusion:Long-term administration of TMZ may lead to serum ions disturbance.Besides the myelosuppression,we should pay attention to the alteration in serum ions concentration,and give patients proper symptomatic treatment when necessary.展开更多
Glioblastoma(GBM)is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months.Current standard-of-care for GBM consists of gross total surgical resect...Glioblastoma(GBM)is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months.Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy.Temozolomide(TMZ)is the first-choice chemotherapeutic agent in GBM;however,the development of resistance to TMZ often becomes the limiting factor in effective treatment.While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance,many other molecular mechanisms have come to light in recent years.Key emerging mechanisms include the involvement of other DNA repair systems,aberrant signaling pathways,autophagy,epigenetic modifications,microRNAs,and extracellular vesicle production.This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.展开更多
基金supported by the National Key Research and Development Programs of China(Grant No.2018YFA0209700)National Natural Science Foundation of China(Grant No.22077073)+1 种基金Frontiers Science Center for New Organic Matter,Nankai University(Grant No.63181206)the Fundamental Research Funds for the Central Universities,Nankai University(Grant No.63206015)。
文摘Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.
基金supported by the Science and Technology Development Fund(Grant Nos.:0007/2020/A1 and 0020/2022/A1)the State Key Laboratory of Quality Research in Chinese Medicine,University of Macao(Grant No.:SKL-QRCM(UM)-2020-2022)+4 种基金the University of Macao(Grant Nos.:MYRG2019-00002-ICMS and MYRG2020-00017-ICMS)2022 Internal Research Grant of SKLQRCM(University of Macao)(Grant No.:QRCM-IRG2022-011)the National Natural Science Foundation of China(Grant No.:22101230)the Natural Science Basic Research Program of Shaanxi(Grant No.:2021JQ-089)the Natural Science Foundation of Chongqing,China(Grant No.:cstc2021jcyj-msxmX0659).
文摘Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.
文摘Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.
基金supported by grants from National Natural Science Foundation of China(Grant No.81372714,81672480,81872065,and 81802506)Liaoning Provincial Natural Science Foundation of China(Grant No.201602244)+3 种基金Liaoning Province Innovation Talents Support Program in Colleges and Universities(Grant No.LR2016023)Distinguished Professor Project of Liaoning ProvinceSpecial Grant for Translational Medicine,Dalian Medical University(Grant No.2015002)Basic Research Projects in Colleges and Universities of Liaoning Province(Grant No.LQ2017033)。
文摘Objective:Temozolomide(TMZ)is commonly used for glioblastoma multiforme(GBM)chemotherapy.However,drug resistance limits its therapeutic effect in GBM treatment.RNA-binding proteins(RBPs)have vital roles in posttranscriptional events.While disturbance of RBP-RNA network activity is potentially associated with cancer development,the precise mechanisms are not fully known.The SNRPG gene,encoding small nuclear ribonucleoprotein polypeptide G,was recently found to be related to cancer incidence,but its exact function has yet to be elucidated.Methods:SNRPG knockdown was achieved via short hairpin RNAs.Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG.Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues.Results:The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53.In addition,the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent.Furthermore,SNRPG was increased in TMZ-resistant GBM cells,and downregulation of SNRPG potentially sensitized resistant cells to TMZ,suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.Our data confirmed that SNRPG suppression sensitizes GBM cells to TMZ by targeting Myc via the p53 signaling cascade.Conclusions:These results indicated that SNRPG is a probable molecular target of GBM and suggested that suppressing SNRPG in resistant GBM cells might be a substantially beneficial method for overcoming essential drug resistance.
基金supported by the National Natural Sciences Foundation of China[31870851 and 31471953]the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences[2019PT320005]+1 种基金the Science and Technology Research Project of Gansu Province[145RTSA012 and 20JR5RA555]the Youth Innovation Promotion Association CAS[2021415]
文摘Objective To investigate the function of primary cilia in regulating the cellular response to temozolomide(TMZ)and ionizing radiation(IR)in glioblastoma(GBM).Methods GBM cells were treated with TMZ or X-ray/carbon ion.The primary cilia were examined by immunostaining with Arl13 b andγ-tubulin,and the cellular resistance ability was measured by cell viability assay or survival fraction assay.Combining with cilia ablation by IFT88 depletion or chloral hydrate and induction by lithium chloride,the autophagy was measured by acridine orange staining assay.The DNA damage repair ability was estimated by the kinetic curve ofγH2 AX foci,and the DNAdependent protein kinase(DNA-PK)activation was detected by immunostaining assay.Results Primary cilia were frequently preserved in GBM,and the induction of ciliogenesis decreased cell proliferation.TMZ and IR promoted ciliogenesis in dose-and time-dependent manners,and the suppression of ciliogenesis significantly enhanced the cellular sensitivity to TMZ and IR.The inhibition of ciliogenesis elevated the lethal effects of TMZ and IR via the impairment of autophagy and DNA damage repair.The interference of ciliogenesis reduced DNA-PK activation,and the knockdown of DNA-PK led to cilium formation and elongation.Conclusion Primary cilia play a vital role in regulating the cellular sensitivity to TMZ and IR in GBM cells through mediating autophagy and DNA damage repair.
基金Scientific Research Project of Science and Technology Committee of Shanghai Municipality, 14DZ1930303
文摘High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemotherapy. Alkylating agent temozolomide has been established as the standard chemotherapy while its resistance inevitable during treatment. This phenomenon seriously influences the prognosis of patients suffering from high grade gliomas. This review aims to elucidate temozolomide chemoresistance mechanisms through three chapters including O^6-methylguanine-DNA methyltransferase(MGMT) methylation, mismatch repair mutation and epigenetic regulation consisting of p21, chromatin and histone, Y-box binding protein-1 and micro RNAs.
文摘BACKGROUND Neuroendocrine carcinoma of the breast(NECB)is a rare type of malignant tumor.Due to the rarity of NECB,the relevant literature mostly comprises case reports.Available data on treatment options for NECB are very limited.CASE SUMMARY A 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography(CT)imaging.She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital.The patient initially presented with a painful lesion of the right breast.She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy.She was regularly followed every 3 mo after surgery.Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm×6.3 cm.Chest CT revealed masses in the anterior chest wall and lung.Core needle biopsy of the lesion revealed liver metastases of NECB.A bone scan showed right second anterior rib metastases.Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor.She stopped receiving endocrine therapy and then received etoposide and cisplatin(EP)chemotherapy as a firstline treatment regimen for six cycles at our hospital after liver,bone,and lung metastases.On October 2017,the chemotherapy regimen was changed to S-1(40mg twice daily,days 1-14)combined with temozolomide(200 mg once daily,days 10-14)(STEM)every 21 d as a second-line treatment regimen due to disease progression.Progression-free survival(PFS)and adverse effects after treatment were analyzed,and the efficacy of the STEM regimen was assessed using RECIST version 1.1.This patient achieved a partial response after using the STEM regimen,with a PFS of 23 mo.Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.CONCLUSION This case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB.STEM is still highly effective in patients who show disease progression with the EP regimen.More evidence is needed to prove the validity of STEM.
文摘Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.
文摘Objective: To investigate the role of adiponectin in human glioma cell lines against the temozolomide and the molecular regulation mechanism. Methods: Human glioma cell lines U251 and U-87MG were cultured in Dulbecco’s modified eagle medium (DMEM) containing 4500 mg/L glucose. MTT was used to measure cell growth ratio. Western blot was used to detect the protein levels of autophagy-related protein (Beclin 1, LC3 I/II, p62) and phosphorylated AMPK (p-AMPK) in human glioma cell lines. After AICAR and Compound C were administered, the change of p-AMPK and the autophagy level were examined by western blot. Results: While adiponectin stimulates AMPK in phosphatase and up-regulates the level of autophagy, human glioma cell lines obtain more resistance against the temozolomide, which is facilitated by AICAR and weakened by Compound C. Conclusion: As an important adipokine, adiponectin can up-regulate the glioma cell autophagy by activating the AMPK signaling pathway which increases the resistance of glioma cells to temozolomide.
文摘The multifocal glioblastomas (GBM) are tumors with multiple discrete areas of contrast enhancing tumors which have considerably poorer prognosis than solitary GBM. Median overall survival of diagnosed patients almost twice as less than solitary presentation. We present a case report of multifocal GBM. A 72-year old right-handed male was evaluated at the Neuro-Oncology Clinic of Baylor Scott and White Hospital (Central Division). Patient presented at this hospital because of persistent progressive headaches, confusion, and an incident of fall. Physical evaluation revealed neurological impairments. Brain magnetic resonance imaging (MRI) revealed heterogeneous contrast enhancing lesions with associated vasogenic oedema. Patient underwent a stereotactic biopsy analysis of the larger lesion and pathology evaluation concluded an isocitrate dehydrogenase 1 and 2 wild type GBM with unmethylated O-6-methylguanine- DNA methyltransferase. Treatment remedies: Patient received 4 weeks concurrent radiation therapy along with combination of temozolomide at dose of 75 mg/m^2 followed adjuvant temozolomide for 10 cycles with bevacizumab at 10 mg/kg every 2 weeks and Optune treatment. Post treatment evaluation: Repeat MRIs showed near complete resolution of the tumors at 26 months of treatment along with improvement of neurological status. Conclusion: Due to limitations of surgical manipulations in multifocal GBM diagnosed patients, combinational chemo and radiation therapy is the treatment of choice for most cases. Using additional novel treatment with non-invasive therapeutic device proven to be effective is another excellent approach to the established practice. Therefore, combination therapy of Optune plus temozolomide and bevacizumab might be a promising remedy for newly diagnosed multifocal glioblastomas.
文摘[Objectives] To observe the clinical efficacy,adverse reaction and survival time of temozolomide combined with whole brain radiotherapy in the treatment of lung cancer. [Methods] A total of 43 patients with lung cancer and cerebral metastases were reviewed and analyzed. Three-dimensional conformal radiotherapy(3D-CRT) technique was used to perform whole brain radiotherapy,one time a day and5 times a week. At the same time of radiotherapy,temozolomide chemotherapy was performed,150 mg/( m2·d),continuous oral administration of 5 d,every 28 days were a cycle( those patients who continue receiving temozolomide chemotherapy did not receive other related antitumor therapy,such as systemic chemotherapy and molecular targeted therapy,etc.),and drugs were administered for 4-6 cycles according to tolerance of patients. Kaplan-Meier method was used to calculate the survival rate. [Results]The objective response rate of 43 patients was79. 0%(34/43),in which CR was 6/43,PR was 28/43,and 9 cases had PD. By December 31,2016,7 patients in 43 cases died,one patient died of cerebral hernia due to intracranial lesions and 6 patients died of failure of other important organs due to metastasis. The OS and PFS of the whole group of patients in one year were 49. 1% and 56. 9% respectively. The adverse reactions were mild and the patients could tolerate such treatment. [Conclusions] Temozolomide combined with whole brain radiotherapy in the treatment of lung cancer with cerebral metastases has excellent clinical efficacy,while patients can tolerate such treatment.
文摘Objective:To investigate the expression level of long chain non coding RNAH19 in advanced gliomas and its relationship with glioma cell temozolomide (TMZ) resistance, and make a preliminary study on their related mechanism.Methods:Tissue samples of normal brain tissue, early onset and recurrence of high grade gliomas were collected, and the expression of LNC H19 was detected by reverse transcription polymerase chain reaction (RT-PCR). The construction of Resistant U251 TMZ Resistant (U251-TR) Cell Lines were completed by intermittent concentration gradient increments and verified by MTT method. The changes in the expression of LncRNA H19 was detected by RT-PCR, lovirus transfection was used to construct U251-TR cell line with stable interference with LNC H19 (U251-TRsiLNC H19), and MTT assay was used to observe the changes of TMZ half-maximal inhibitory concentration (IC50). Western Blot and RT-PCR were used to detect the changes of O6-methylguanine DNA methyltransferase (MGMT) in U251, U251-TR and U251-TRsiLNC H19.Results: The results of RT-PCR showed that the expression of LNC H19 in high-grade glioma was significantly higher than that in primary glioma tissue and normal brain tissue. The IC50 value and drug resistance index of U251-TR cell line were significantly increased, the expression of LncRNA H19 in U251-TR cell line was significantly higher than that in U251 cells and the expression of MGMT were also increased. We succeeded in interfering with the expression of LNC H19 in the U251-TR cell line, and found that the IC50 value and drug resistance index of U251-TR cell line were decreased significantly and the expression of MGMT were also decreased.Conclusion:LNC H19 is highly expressed in recurrent high-grade gliomas, which may increase the level of MGMT, leading to the occurrence of glioma cell TMZ resistance. LNC H19 is a key factor in the occurrence of TMZ resistance in glioma cells.
基金supported by Scientific and Technological Research Council of Turkey(TUBITAK),“2209/A-University Students Research Projects Support Program”(Grant No.1919B011601865).
文摘Background and Aim: In this study, it was aimed to examine the cytotoxic effect of temozolomide (TMZ) treatment, on MCF-7 and SKBR3 cell lines, to study the methylation levels of MGMT gene expression and gene promoter region. Methods: The MTT test was performed to determine the effective dose of TMZ. The time-dependent cell survival test was performed after the IC50 value was found. Western blotting was performed to determine MGMT gene expression levels. High Resolution Melting (HRM) technique was used to determine the methylation levels of MGMT gene promoter region. Results: TMZ has been shown to have a high cytotoxic effect on SKBR3 cell line and low cytotoxicity on MCF-7. When MGMT expression levels before and after TMZ treatment were observed by western blotting, the gene expression levels of TMZ treatment were shown to decrease in both cell lines. It was observed that MGMT gene promoter region was hypermethylated in two cell lines, and that the application of TMZ further increased the methylation levels in the promoter region. Conclusions: It was seen that TMZ could be used as a single agent in SKBR-3 cell line. With this study on breast cancer, it is expected that temozolomide treatment will lead future in vitro and in vivo studies for breast cancer.
文摘Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods A total of 40 patients with pathologically confirmed malignant gliomas were enrolled. All patients had pretreated with radiotherapy and had assessable lesions.
文摘Objective To explore the effective treatment for refractory piuitary adenomas. Methods Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to temozolomide,we treated a refractory pituitary adenoma patient. Results MGMT expression in this case was at low level,and primary pituitary adenoma cells were sensitive to temozolomide in vitro. The tumor volume
基金supported by grants from the Department of Science and Technology of Sichuan Province,China(No.23ZDYF2212,23ZDYF2098)the Foundation for Sichuan Provincial People's Hospital(Sichuan,China)(No.2022QN06)Medico-Engineering Cooperation Funds from the University of Electronic Science and Technology of China(No.ZYGX2021YGLH209)and 2022 Tianfu Qingcheng Project,China.
文摘Glioma is a common tumor originating in the brain that has a high mortality rate.Temozolomide(TMZ)is the first-line treatment for high-grade gliomas.However,a large pro-portion of gliomas are resistant to TMZ,posing a great challenge to their treatment.In the study,the specific functions and mechanism(s)by which cortistatin(CORT)regulates TMZ resis-tance and glioma progression were evaluated.The decreased expression of CoRT was detected in glioma tissues,and highly expressed CORT was associated with a better survival rate in pa-tients with glioma.CORT overexpression notably decreased the capacity of glioma cells to pro-liferate and migrate in vitro and to form tumors in vivo.CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT,p21,and Puma expression.Importantly,CORT overexpression reduced the resistance of gliomas to TMZ in vivo.CORT expression Was negatively correlated with MGMT expression in both glioma tissues and cells,and it was found that CORT inhibited NF-kB pathway activation in glioma cells,thereby inhibiting MGMT expression.In conclusion,CORT regulates glioma cell growth,migration,apoptosis,and TMZ resistance by weakening the activity of NF-kB/p65 and thereby regulating MGMT expression.The CORT/NF-kB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ.Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells,independent of its effects on TMZ resistance,providing evidence of novel therapeutic targets for glioma that should be evaluated infurther studies.
基金These studies were supported from the Gittlen Foundation.
文摘Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of O6-methylguanine methyltransferase(MGMT)and/or lack of a DNA repair pathway in GBM cells.Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics.However,the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared.This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines.It also summarizes potential treatment options for TMZ resistant GBMs.
基金This work was primarily supported by Grants from the National Natural Science Foundation of China(NSFC-81972360)
文摘Background:High-grade glioma(HGG)is a fatal human cancer.Bortezomib,a proteasome inhibitor,has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation.This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas.Methods:U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay,tumor cell spheroid growth,and colony formation assay.Cell apoptosis and cell cycle were detected by flow cytometry.Temozolomide(TMZ)-insensitive cell lines were induced by long-term TMZ treatment,and cells with stem cell characteristics were enriched with stem cell culture medium.The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction,and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections.Via inoculating U87 cells subcutaneously,glioma xenograft models in nude mice were established for drug experiments.Patient survival data were analyzed using the Kaplan-Meier method.Results:Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose-and time-dependent manner by inducing apoptosis and cell cycle arrest.Bortezomib also significantly inhibited the spheroid growth,colony formation,and stem-like cell proliferation of U251 and U87 cells.When administrated in combination,bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo.Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1(FOXM1)and its target gene Survivin.The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients.Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor progno-sis in glioma patients.Conclusions:Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy,probably via down-regulating the FOXM1-Survivin axis.Bortezomib might be a promising agent for treating malignant glioma,alone or in combination with TMZ.
基金This work was supported by funding from the National Key Research and Development Plan(No. 2016YFC0902500)the National Natural Science Foundation of China(No. 81903060)the Cultivation Plan of Beijing Hospital Management Center(PX2021025)
文摘Background:Adjuvant temozolomide(TMZ)chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma(HGG).However,the influence of long-term TMZ chemotherapy on serum ions concentration is unclear.Methods:One hundred and thirty-eight patients with HGG were included.Their blood samples were collected for blood biochemistry and routine test.The alteration in serum ions concentration,total protein,albumin,globin,and blood cells counts were used to identify the impact of long-term TMZ chemotherapy.Results:Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles,we identified that serum potassium concentration had a downward trend after TMZ administration(1st vs.6th,p<0.001;1st vs.12th,p<0.001).Additionally,the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles(r=−0.649,p=0.023).The hematological adverse events mainly centered on grade 1 to 2.Conclusion:Long-term administration of TMZ may lead to serum ions disturbance.Besides the myelosuppression,we should pay attention to the alteration in serum ions concentration,and give patients proper symptomatic treatment when necessary.
文摘Glioblastoma(GBM)is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months.Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy.Temozolomide(TMZ)is the first-choice chemotherapeutic agent in GBM;however,the development of resistance to TMZ often becomes the limiting factor in effective treatment.While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance,many other molecular mechanisms have come to light in recent years.Key emerging mechanisms include the involvement of other DNA repair systems,aberrant signaling pathways,autophagy,epigenetic modifications,microRNAs,and extracellular vesicle production.This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.
