Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a bre...Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a breast cancer lung metastasis(BCLM)-associated gene signature were combined to discover anti-metastatic drugs.After screening of thousands of compounds,we identified Ponatinib as a BCLM inhibitor.Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models.Mechanistically,Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein.Notably,JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients.Collectively,we established a novel approach for the discovery of anti-metastatic drugs,identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM.Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.展开更多
Nanomaterials with unique characteristics exhibit favorable therapeutic and diagnostic properties,implying their enormous potential as biomedical candidates. C60 has been used in gene- and drug-delivery, as imaging ag...Nanomaterials with unique characteristics exhibit favorable therapeutic and diagnostic properties,implying their enormous potential as biomedical candidates. C60 has been used in gene- and drug-delivery, as imaging agents, and as photosensitizers in cancer therapy. In this study, the influences of a cationic functionalized fullerene on cellular behavior of human colorectal cancer cell line(HT-29) were investigated. Results indicated that HT-29 treated with the studied compound showed a lower sensitivity but a significant impairment in migration and invasion by interfering with the activities of matrix metalloproteinases(MMP-2 and9). The presence of fullerene also altered the capacity of adhesion-related proteins to perform their activity,thereby inducing dramatically adverse effects on the cell physiological functions such as cell adhesion. Thus,our study suggests that this compound is a new potential anti-metastatic effector and a therapeutic component for malignant colorectal cancer.展开更多
Aim:Esophageal cancer is one of the major types of cancers,causing death of approximately 5%of all cancer deaths.This is due,in large part,to both relatively ineffectual and unavailable treatment.In order to develop a...Aim:Esophageal cancer is one of the major types of cancers,causing death of approximately 5%of all cancer deaths.This is due,in large part,to both relatively ineffectual and unavailable treatment.In order to develop an effective treatment strategy against esophageal cancer,it is important to target metastatic genes.In the present study,we have used a cancer-associated fibroblast(CAF)cell line derived from culturing peripheral blood mononuclear cells from a metastatic esophageal cancer patient to see whether chitosan nanoparticles(Ch-Np)treatment can modulate the metastatic phenotype of CAF cells by using various cellular and molecular markers.Methods:A CAF cell line was developed from peripheral blood mononuclear cells(PBMC)from a metastatic esophageal cancer patient.The cells were treated with 100μg/mL of chitosan nanoparticle in vitro for the morphological and oncogenic characteristic studies,along with the expression of various genes involved in process of tumor development and metastasis.Techniques such as Light and Phase Contrast Microscopy,cell growth rate,Scratch metastatic assay,and molecular profiling were carried out to see changes in CAF cells before and after Ch-Np treatment.Results:It was observed that CAF cells grew in monolayer and had a doubling time of 25±0.38 h.Morphologically,the cells had a fibroblastic appearance.After treatment with 100μg/mL of Ch-Np in vitro,there was an increased doubling time to 30±0.83 h.Similarly,Scratch Assay showed an inhibition in the metastatic property of these cells.These findings were confirmed with gene expression studies.It was also observed that there was complete down-regulation of metastatic genes MMP1 and MMP9 and chemokines such as CXCR-4,CXCR-7,CCR-5,and SDF-1,indicating that Ch-Np inhibited the metastatic characteristic of CAF cells.Conclusion:This study has shown that there was an inhibition of metastatic properties of CAF cells after treatment with Ch-Np,suggesting that Ch-Np can be a delivery system used for targeting cancer cells for treatment of展开更多
Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therap...Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therapy using polyethylenimine（PEI） as the carrier of Bcl2 siRNA.Most of the DOX and siRNA possessed high cellular uptake efficiency in B16F10 cells,which was proved by FCM and CLSM analysis.Real-time PCR showed that PEI/Bcl2 siRNA exhibited high gene silencing efficiency with 70%Bcl2 mRNA being knocked down.The combination of DOX and siRNA could enhance the cell proliferation inhibition and the cell apoptosis against B16F10 cells compared to free DOX or PEI/Bcl2 siRNA.Furthermore,the biodistribution of DOX and siRNA via pulmonary administration was studied in mice with B16F10 metastatic lung cancer.The results showed that most of the DOX and siRNA were accumulated in lungs and lasted at least for 3 days,which suggested that combined DOX and siRNA by pulmonary administration may have high anti-tumor effects for metastatic lung cancer treatment in vivo.展开更多
基金a grant from the National Natural Science Foundation of China(Grant No.81673460)fun ding from Tsinghua-Peking Joint Center for Life Sciences and Beijing Mun icipal Science&Technology Commissi on.
文摘Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a breast cancer lung metastasis(BCLM)-associated gene signature were combined to discover anti-metastatic drugs.After screening of thousands of compounds,we identified Ponatinib as a BCLM inhibitor.Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models.Mechanistically,Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein.Notably,JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients.Collectively,we established a novel approach for the discovery of anti-metastatic drugs,identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM.Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
基金funded within the research contracts Nanocancer Friuli Venezia Giulia, Fra-2011University of TriesteItalian Ministry of Education MIUR (FIRB RBAP11ETKA and PRIN 2010N3T9M4 001)
文摘Nanomaterials with unique characteristics exhibit favorable therapeutic and diagnostic properties,implying their enormous potential as biomedical candidates. C60 has been used in gene- and drug-delivery, as imaging agents, and as photosensitizers in cancer therapy. In this study, the influences of a cationic functionalized fullerene on cellular behavior of human colorectal cancer cell line(HT-29) were investigated. Results indicated that HT-29 treated with the studied compound showed a lower sensitivity but a significant impairment in migration and invasion by interfering with the activities of matrix metalloproteinases(MMP-2 and9). The presence of fullerene also altered the capacity of adhesion-related proteins to perform their activity,thereby inducing dramatically adverse effects on the cell physiological functions such as cell adhesion. Thus,our study suggests that this compound is a new potential anti-metastatic effector and a therapeutic component for malignant colorectal cancer.
文摘Aim:Esophageal cancer is one of the major types of cancers,causing death of approximately 5%of all cancer deaths.This is due,in large part,to both relatively ineffectual and unavailable treatment.In order to develop an effective treatment strategy against esophageal cancer,it is important to target metastatic genes.In the present study,we have used a cancer-associated fibroblast(CAF)cell line derived from culturing peripheral blood mononuclear cells from a metastatic esophageal cancer patient to see whether chitosan nanoparticles(Ch-Np)treatment can modulate the metastatic phenotype of CAF cells by using various cellular and molecular markers.Methods:A CAF cell line was developed from peripheral blood mononuclear cells(PBMC)from a metastatic esophageal cancer patient.The cells were treated with 100μg/mL of chitosan nanoparticle in vitro for the morphological and oncogenic characteristic studies,along with the expression of various genes involved in process of tumor development and metastasis.Techniques such as Light and Phase Contrast Microscopy,cell growth rate,Scratch metastatic assay,and molecular profiling were carried out to see changes in CAF cells before and after Ch-Np treatment.Results:It was observed that CAF cells grew in monolayer and had a doubling time of 25±0.38 h.Morphologically,the cells had a fibroblastic appearance.After treatment with 100μg/mL of Ch-Np in vitro,there was an increased doubling time to 30±0.83 h.Similarly,Scratch Assay showed an inhibition in the metastatic property of these cells.These findings were confirmed with gene expression studies.It was also observed that there was complete down-regulation of metastatic genes MMP1 and MMP9 and chemokines such as CXCR-4,CXCR-7,CCR-5,and SDF-1,indicating that Ch-Np inhibited the metastatic characteristic of CAF cells.Conclusion:This study has shown that there was an inhibition of metastatic properties of CAF cells after treatment with Ch-Np,suggesting that Ch-Np can be a delivery system used for targeting cancer cells for treatment of
基金the National Natural Science Foundationof China(Nos.51503200,21474104,5123300451520105004 and 51390484)Jilin Province Science and Technology Development Program(No.20160204032GX)the National Program for Support of Top-notch Young Professionals for financial support
文摘Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therapy using polyethylenimine（PEI） as the carrier of Bcl2 siRNA.Most of the DOX and siRNA possessed high cellular uptake efficiency in B16F10 cells,which was proved by FCM and CLSM analysis.Real-time PCR showed that PEI/Bcl2 siRNA exhibited high gene silencing efficiency with 70%Bcl2 mRNA being knocked down.The combination of DOX and siRNA could enhance the cell proliferation inhibition and the cell apoptosis against B16F10 cells compared to free DOX or PEI/Bcl2 siRNA.Furthermore,the biodistribution of DOX and siRNA via pulmonary administration was studied in mice with B16F10 metastatic lung cancer.The results showed that most of the DOX and siRNA were accumulated in lungs and lasted at least for 3 days,which suggested that combined DOX and siRNA by pulmonary administration may have high anti-tumor effects for metastatic lung cancer treatment in vivo.
