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 g展开更多
目的探讨伽玛刀(gamma knife)联合替莫唑胺(temozolomide,TMZ)放化疗治疗原发中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)的疗效及安全性。方法选择2005-06—2016-10山东省安康医院收治的PCNSL患者48例为研究对...目的探讨伽玛刀(gamma knife)联合替莫唑胺(temozolomide,TMZ)放化疗治疗原发中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)的疗效及安全性。方法选择2005-06—2016-10山东省安康医院收治的PCNSL患者48例为研究对象,随机分为2组各24例。对照组采用伽玛刀治疗,联合组在对照组治疗基础上应用TMZ联合治疗。比较2组患者治疗后近期疗效、生活质量及不良反应的发生情况及3 a内患者总生存率(response rate,RR)。结果联合组总生存率87.5%,对照组为54.17%,联合组显著高于对照组,差异有统计学意义(χ^2=4.941,P=0.026<0.05);联合组Karofsky得分(Karnofsky performance status score,KPS)改善率(62.50%)显著高于对照组(33.33%)(χ^2=4.090,P=0.043<0.05);2组恶心呕吐、头痛、白细胞减少、血小板减少和急性脑损伤等不良反应发生率差异均无统计学意义(P>0.05);随访3 a,联合组中位生存时间(median overall survival,mOS)24个月,显著长于对照组的15.5个月,差异有统计学意义(P=0.007)。结论伽玛刀联合TMZ可有效改善PCNSL患者的近远期疗效,具有良好的安全性,且可提高患者的生存质量。展开更多
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 g
文摘目的探讨伽玛刀(gamma knife)联合替莫唑胺(temozolomide,TMZ)放化疗治疗原发中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)的疗效及安全性。方法选择2005-06—2016-10山东省安康医院收治的PCNSL患者48例为研究对象,随机分为2组各24例。对照组采用伽玛刀治疗,联合组在对照组治疗基础上应用TMZ联合治疗。比较2组患者治疗后近期疗效、生活质量及不良反应的发生情况及3 a内患者总生存率(response rate,RR)。结果联合组总生存率87.5%,对照组为54.17%,联合组显著高于对照组,差异有统计学意义(χ^2=4.941,P=0.026<0.05);联合组Karofsky得分(Karnofsky performance status score,KPS)改善率(62.50%)显著高于对照组(33.33%)(χ^2=4.090,P=0.043<0.05);2组恶心呕吐、头痛、白细胞减少、血小板减少和急性脑损伤等不良反应发生率差异均无统计学意义(P>0.05);随访3 a,联合组中位生存时间(median overall survival,mOS)24个月,显著长于对照组的15.5个月,差异有统计学意义(P=0.007)。结论伽玛刀联合TMZ可有效改善PCNSL患者的近远期疗效,具有良好的安全性,且可提高患者的生存质量。