Pub Date : 2019-12-01Epub Date: 2019-09-06DOI: 10.1007/s13402-019-00471-x
Peichen Zhang, Lingyan Shi, Tingting Zhang, Lin Hong, Wei He, Peihai Cao, Xin Shen, Peisen Zheng, Yiqun Xia, Peng Zou
Purpose: Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells.
Methods: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo.
Results: We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment.
Conclusions: Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.
{"title":"Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells.","authors":"Peichen Zhang, Lingyan Shi, Tingting Zhang, Lin Hong, Wei He, Peihai Cao, Xin Shen, Peisen Zheng, Yiqun Xia, Peng Zou","doi":"10.1007/s13402-019-00471-x","DOIUrl":"10.1007/s13402-019-00471-x","url":null,"abstract":"<p><strong>Purpose: </strong>Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells.</p><p><strong>Methods: </strong>Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo.</p><p><strong>Results: </strong>We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment.</p><p><strong>Conclusions: </strong>Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"847-860"},"PeriodicalIF":6.6,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00471-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46083132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-01Epub Date: 2019-07-22DOI: 10.1007/s13402-019-00461-z
Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li
Purpose: Exosomes play important roles in intercellular communication through signaling pathways affecting tumor microenvironment modulation and tumor proliferation, including those in glioblastoma (GBM). As yet, however, limited studies have been conducted on the inhibitory effect of human bone marrow-derived mesenchymal stem cell (hBMSC)-derived exosomes on GBM development. Therefore, we set out to assess the role of hBMSC secreted exosomes, in particular those carrying microRNA-34a (miR-34a), in the development of GBM.
Methods: Microarray-based expression analysis was employed to identify differentially expressed genes and to predict miRNAs regulating MYCN expression. Next, hBMSCs were transfected with a miR-34a mimic or inhibitor after which exosomes were isolated. Proliferation, apoptosis, migration, invasion and temozolomide (TMZ) chemosensitivity of exosome-exposed GBM cells (T-98G, LN229 and A-172) were measured in vitro. The mechanism underlying MYCN regulation was investigated using lentiviral transfections. The in vivo inhibitory effect of exosomal miR-34a was measured in nude mice xenografted with GBM cells through subcutaneous injection of hBMSCs with an upregulated miR34a content.
Results: We found that poorly-expressed miR-34a specifically targeted and negatively regulated the expression of MYCN in GBM cells. In addition we found that miR-34a was delivered to T-98G, LN229 and A-172 GBM cells via hBMSC-derived exosomes. Exogenous overexpression of miR-34a in hBMSC-derived exosomes resulted in inhibition of GBM cell proliferation, invasion, migration and tumorigenesis in vitro and in vivo, while promoting the chemosensitivity of GBM cells to TMZ by silencing MYCN.
Conclusions: From our data we conclude that hBMSC-derived exosomes overexpressing miR-34a may be instrumental for the therapeutic targeting and clinical management of GBM.
{"title":"Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN.","authors":"Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li","doi":"10.1007/s13402-019-00461-z","DOIUrl":"https://doi.org/10.1007/s13402-019-00461-z","url":null,"abstract":"<p><strong>Purpose: </strong>Exosomes play important roles in intercellular communication through signaling pathways affecting tumor microenvironment modulation and tumor proliferation, including those in glioblastoma (GBM). As yet, however, limited studies have been conducted on the inhibitory effect of human bone marrow-derived mesenchymal stem cell (hBMSC)-derived exosomes on GBM development. Therefore, we set out to assess the role of hBMSC secreted exosomes, in particular those carrying microRNA-34a (miR-34a), in the development of GBM.</p><p><strong>Methods: </strong>Microarray-based expression analysis was employed to identify differentially expressed genes and to predict miRNAs regulating MYCN expression. Next, hBMSCs were transfected with a miR-34a mimic or inhibitor after which exosomes were isolated. Proliferation, apoptosis, migration, invasion and temozolomide (TMZ) chemosensitivity of exosome-exposed GBM cells (T-98G, LN229 and A-172) were measured in vitro. The mechanism underlying MYCN regulation was investigated using lentiviral transfections. The in vivo inhibitory effect of exosomal miR-34a was measured in nude mice xenografted with GBM cells through subcutaneous injection of hBMSCs with an upregulated miR34a content.</p><p><strong>Results: </strong>We found that poorly-expressed miR-34a specifically targeted and negatively regulated the expression of MYCN in GBM cells. In addition we found that miR-34a was delivered to T-98G, LN229 and A-172 GBM cells via hBMSC-derived exosomes. Exogenous overexpression of miR-34a in hBMSC-derived exosomes resulted in inhibition of GBM cell proliferation, invasion, migration and tumorigenesis in vitro and in vivo, while promoting the chemosensitivity of GBM cells to TMZ by silencing MYCN.</p><p><strong>Conclusions: </strong>From our data we conclude that hBMSC-derived exosomes overexpressing miR-34a may be instrumental for the therapeutic targeting and clinical management of GBM.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 6","pages":"783-799"},"PeriodicalIF":6.6,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00461-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-12DOI: 10.1007/s13402-019-00476-6
Zhiyong Yang, Ning Zhao, J. Cui, Heshui Wu, J. Xiong, T. Peng
{"title":"Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210","authors":"Zhiyong Yang, Ning Zhao, J. Cui, Heshui Wu, J. Xiong, T. Peng","doi":"10.1007/s13402-019-00476-6","DOIUrl":"https://doi.org/10.1007/s13402-019-00476-6","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"11 1","pages":"123 - 136"},"PeriodicalIF":6.6,"publicationDate":"2019-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00476-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52880080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-13DOI: 10.1007/s13402-019-00435-1
Chao Song, Tianwei Chen, Lan He, Ning Ma, Jian-ang Li, Y. Rong, Yuan Fang, Mengmeng Liu, D. Xie, W. Lou
{"title":"PRMT1 promotes pancreatic cancer growth and predicts poor prognosis","authors":"Chao Song, Tianwei Chen, Lan He, Ning Ma, Jian-ang Li, Y. Rong, Yuan Fang, Mengmeng Liu, D. Xie, W. Lou","doi":"10.1007/s13402-019-00435-1","DOIUrl":"https://doi.org/10.1007/s13402-019-00435-1","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"43 1","pages":"51 - 62"},"PeriodicalIF":6.6,"publicationDate":"2019-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00435-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52880035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-07DOI: 10.1007/s13402-019-00472-w
N. Mizoshiri, T. Shirai, R. Terauchi, S. Tsuchida, Y. Mori, Daichi Hayashi, T. Kishida, Y. Arai, O. Mazda, T. Nakanishi, T. Kubo
{"title":"The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma","authors":"N. Mizoshiri, T. Shirai, R. Terauchi, S. Tsuchida, Y. Mori, Daichi Hayashi, T. Kishida, Y. Arai, O. Mazda, T. Nakanishi, T. Kubo","doi":"10.1007/s13402-019-00472-w","DOIUrl":"https://doi.org/10.1007/s13402-019-00472-w","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"861 - 871"},"PeriodicalIF":6.6,"publicationDate":"2019-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00472-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43622790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-08DOI: 10.1007/s13402-019-00465-9
Á. Quintanal-Villalonga, S. Molina-Pinelo
{"title":"Epigenetics of lung cancer: a translational perspective","authors":"Á. Quintanal-Villalonga, S. Molina-Pinelo","doi":"10.1007/s13402-019-00465-9","DOIUrl":"https://doi.org/10.1007/s13402-019-00465-9","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"739 - 756"},"PeriodicalIF":6.6,"publicationDate":"2019-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00465-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45665050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-07DOI: 10.1007/s13402-019-00467-7
Federico Rossari, Cristina Zucchinetti, G. Buda, E. Orciuolo
{"title":"Tumor dormancy as an alternative step in the development of chemoresistance and metastasis - clinical implications","authors":"Federico Rossari, Cristina Zucchinetti, G. Buda, E. Orciuolo","doi":"10.1007/s13402-019-00467-7","DOIUrl":"https://doi.org/10.1007/s13402-019-00467-7","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"43 1","pages":"155 - 176"},"PeriodicalIF":6.6,"publicationDate":"2019-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00467-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52880058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-02DOI: 10.1007/s13402-019-00464-w
Ada Koschorke, S. Faraci, Debora Giani, C. Chiodoni, E. Iorio, R. Canese, M. Colombo, A. Lamolinara, M. Iezzi, M. Ladomery, Claudio Vernieri, F. de Braud, M. Di Nicola, E. Tagliabue, L. Castagnoli, S. Pupa
{"title":"Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment","authors":"Ada Koschorke, S. Faraci, Debora Giani, C. Chiodoni, E. Iorio, R. Canese, M. Colombo, A. Lamolinara, M. Iezzi, M. Ladomery, Claudio Vernieri, F. de Braud, M. Di Nicola, E. Tagliabue, L. Castagnoli, S. Pupa","doi":"10.1007/s13402-019-00464-w","DOIUrl":"https://doi.org/10.1007/s13402-019-00464-w","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"815 - 828"},"PeriodicalIF":6.6,"publicationDate":"2019-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00464-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45021529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}