Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblasto...Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma cells.Methods Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,respectively.Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was explored.Results Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-2.In addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin pathway.This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.展开更多
The rapidly developing resistance of cancers to chemotherapy agents and the severe cytotoxicity of such agents to normal cells are major stumbling blocks in current cancer treatments.Most current chemotherapy agents h...The rapidly developing resistance of cancers to chemotherapy agents and the severe cytotoxicity of such agents to normal cells are major stumbling blocks in current cancer treatments.Most current chemotherapy agents have significant cytotoxicity,which leads to devastating adverse effects and results in a substandard quality of life,including increased daily morbidity and premature mortality.The death receptor of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)can sidestep p53-dependent pathways to induce tumor cell apoptosis without damaging most normal cells.However,various cancer cells can develop resistance to TRAIL-induced apoptosis via different pathways.Therefore,it is critical to find an efficient TRAIL sensitizer to reverse the resistance of tumor cells to TRAIL,and to reinforce TRAIL’s ability to induce tumor cell apoptosis.In recent years,traditional Chinese medicines and their active ingredients have shown great potential to trigger apoptotic cell death in TRAIL-resistant cancer cell lines.This review aims to collate information about Chinese medicines that can effectively reverse the resistance of tumor cells to TRAIL and enhance TRAIL’s ability to induce apoptosis.We explore the therapeutic potential of TRAIL and provide new ideas for the development of TRAIL therapy and the generation of new anticancer drugs for human cancer treatment.This study involved an extensive review of studies obtained from literature searches of electronic databases such as Google Scholar and PubMed."TRAIL sensitize"and"Chinese medicine"were the search keywords.We then isolated newly published studies on the mechanisms of TRAIL-induced apoptosis.The name of each plant was validated using certified databases such as The Plant List.This study indicates that TRAIL can be combined with different Chinese medicine components through intrinsic or extrinsic pathways to promote cancer cell apoptosis.It also demonstrates that the active ingredients of traditional Chinese medicines enhance the sensitivity of cancer cells to TRAIL-mediated apoptosis.This provides useful information regarding traditional Chinese medicine treatment,the development of TRAIL-based therapies,and the treatment of cancer.展开更多
Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung,leading to sharply reduced patients'survival rate.Effectively treating these tumors thus could improve late stage melanoma wit...Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung,leading to sharply reduced patients'survival rate.Effectively treating these tumors thus could improve late stage melanoma with lung metastasis.In this study,we fabricated a Cys-Arg-Glu-Lys-Ala with N-methylated Glu(CR(NMe)EKA)decorated disk shaped nano vehicle to co-deliver tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and paclitaxel(PTX)to lung melanoma tumor sites(TRAIL-[ND-PTX]^(CR(NMe)EKA)).These nanodisks displayed better tumor-targeting and penetration capability than spherical nanoparticles,while the fibronectin-targeting CR(NMe)EKA motif also increased the tumor accumulation of loaded drugs.The combined usage of TRAIL and PTX both killed tumor cells and reduced local nutrition supply,leading to stronger overall anti-tumor effect.This TRAIL-[ND-PTX]^(CR(NMe)EKA)system performed remarkably better than free paclitaxel and also significantly elongated survival rate of melanoma lung metastasis bearing mice,without displaying significant toxicity.Hence,this designing strategy and the fabricated nanoplatform possess potential for further development.展开更多
Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigene...Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription.In this review,we provide an overview of recent studies on the role of histone modifications in carcinogenesis.Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)are well-considered as promising anti-tumour therapies,we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers.In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.展开更多
基金Supported by Scientific and Technological Research Programme of Chongqing Municipal Education Commission,China(No.KJ130320)。
文摘Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma cells.Methods Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,respectively.Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was explored.Results Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-2.In addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin pathway.This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110167),China。
文摘The rapidly developing resistance of cancers to chemotherapy agents and the severe cytotoxicity of such agents to normal cells are major stumbling blocks in current cancer treatments.Most current chemotherapy agents have significant cytotoxicity,which leads to devastating adverse effects and results in a substandard quality of life,including increased daily morbidity and premature mortality.The death receptor of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)can sidestep p53-dependent pathways to induce tumor cell apoptosis without damaging most normal cells.However,various cancer cells can develop resistance to TRAIL-induced apoptosis via different pathways.Therefore,it is critical to find an efficient TRAIL sensitizer to reverse the resistance of tumor cells to TRAIL,and to reinforce TRAIL’s ability to induce tumor cell apoptosis.In recent years,traditional Chinese medicines and their active ingredients have shown great potential to trigger apoptotic cell death in TRAIL-resistant cancer cell lines.This review aims to collate information about Chinese medicines that can effectively reverse the resistance of tumor cells to TRAIL and enhance TRAIL’s ability to induce apoptosis.We explore the therapeutic potential of TRAIL and provide new ideas for the development of TRAIL therapy and the generation of new anticancer drugs for human cancer treatment.This study involved an extensive review of studies obtained from literature searches of electronic databases such as Google Scholar and PubMed."TRAIL sensitize"and"Chinese medicine"were the search keywords.We then isolated newly published studies on the mechanisms of TRAIL-induced apoptosis.The name of each plant was validated using certified databases such as The Plant List.This study indicates that TRAIL can be combined with different Chinese medicine components through intrinsic or extrinsic pathways to promote cancer cell apoptosis.It also demonstrates that the active ingredients of traditional Chinese medicines enhance the sensitivity of cancer cells to TRAIL-mediated apoptosis.This provides useful information regarding traditional Chinese medicine treatment,the development of TRAIL-based therapies,and the treatment of cancer.
基金supported by the Regional Innovation and Development Joint Fund(No.U20A20441)the National Science Fund for Excellent Young Scholars(No.82022070).
文摘Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung,leading to sharply reduced patients'survival rate.Effectively treating these tumors thus could improve late stage melanoma with lung metastasis.In this study,we fabricated a Cys-Arg-Glu-Lys-Ala with N-methylated Glu(CR(NMe)EKA)decorated disk shaped nano vehicle to co-deliver tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and paclitaxel(PTX)to lung melanoma tumor sites(TRAIL-[ND-PTX]^(CR(NMe)EKA)).These nanodisks displayed better tumor-targeting and penetration capability than spherical nanoparticles,while the fibronectin-targeting CR(NMe)EKA motif also increased the tumor accumulation of loaded drugs.The combined usage of TRAIL and PTX both killed tumor cells and reduced local nutrition supply,leading to stronger overall anti-tumor effect.This TRAIL-[ND-PTX]^(CR(NMe)EKA)system performed remarkably better than free paclitaxel and also significantly elongated survival rate of melanoma lung metastasis bearing mice,without displaying significant toxicity.Hence,this designing strategy and the fabricated nanoplatform possess potential for further development.
基金This research was partly funded by The Dutch Technology Foundation(STW)(No.11056)European Fund for Regional Development(KOP/EFRO)(No.068 and No.073).
文摘Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription.In this review,we provide an overview of recent studies on the role of histone modifications in carcinogenesis.Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)are well-considered as promising anti-tumour therapies,we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers.In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.
