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
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
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
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.
