Effect of low doses of actinomycin D on neuroblastoma cell lines
Background: Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. W...
| Autores: | ; ; ; ; ; ; ; ; |
|---|---|
| Tipo de documento: | Artigo |
| Estado: | Published version |
| Data de publicação: | 2016 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositório: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/111079 |
| Acesso em linha: | https://hdl.handle.net/2445/111079 |
| Nível de acesso: | Acesso aberto |
| Palavra-chave: | Actinomicetals Apoptosi Cèl·lules Posologia Infants Actinomycetales Apoptosis Cells Posology Children |
| _version_ | 1878735356334964736 |
|---|---|
| author | Cortés, Constanza |
| author2 | Veiga, Sonia Rosa Pereira da Almacellas i Canals, Eugènia Hernández-Losa, Javier Ferreres, Joan C. Kozma, Sara C. Ambrosio Viale, Santiago Thomas, George Tauler Girona, Albert |
| author2_role | author author author author author author author author |
| author_browse | Almacellas i Canals, Eugènia Ambrosio Viale, Santiago Cortés, Constanza Ferreres, Joan C. Hernández-Losa, Javier Kozma, Sara C. Tauler Girona, Albert Thomas, George Veiga, Sonia Rosa Pereira da |
| author_facet | Cortés, Constanza Veiga, Sonia Rosa Pereira da Almacellas i Canals, Eugènia Hernández-Losa, Javier Ferreres, Joan C. Kozma, Sara C. Ambrosio Viale, Santiago Thomas, George Tauler Girona, Albert |
| author_role | author |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| description | Background: Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. With the intent to find new therapies for neuroblastomas, we investigated the efficacy of low-doses of actinomycin D, which at low concentrations preferentially inhibit RNA polymerase I-dependent rRNA trasncription and therefore, ribosome biogenesis. Methods: Neuroblastoma cell lines with different p53 genetic background were employed to determine the response on cell viability and apoptosis of low-dose of actinomycin D. Subcutaneously-implanted SK-N-JD derived neuroblastoma tumors were used to assess the effect of low-doses of actinomycin D on tumor formation. Results: Low-dose actinomycin D treatment causes a reduction of cell viability in neuroblastoma cell lines and that this effect is stronger in cells that are wild-type for p53. MYCN overexpression contributes to enhance this effect, confirming the importance of this oncogene in ribosome biogenesis. In the wild-type SK-N-JD cell line, apoptosis was the major mechanism responsible for the reduction in viability and we demonstrate that treatment with the MDM2 inhibitor Nutlin-3, had a similar effect to that of actinomycin D. Apoptosis was also detected in p53(-/-)deficient LA1-55n cells treated with actinomycin D, however, only a small recovery of cell viability was found when apoptosis was inhibited by a pan-caspase inhibitor, suggesting that the treatment could activate an apoptosis-independent cell death pathway in these cells. We also determined whether actinomycin D could increase the efficacy of the histone deacetylase inhibitor, SAHA, which is in being used in neuroblastoma clinical trials. We show that actinomycin D synergizes with SAHA in neuroblastoma cell lines. Moreover, on subcutaneously-implanted neuroblastoma tumors derived from SK-N-JD cells, actinomycin D led to tumor regression, an effect enhanced in combination with SAHA. Conclusions: The results presented in this work demonstrate that actinomycin D, at low concentrations, inhibits proliferation and induces cell death in vitro, as well as tumor regression in vivo. From this study, we propose that use of ribosome biogenesis inhibitors should be clinically considered as a potential therapy to treat neuroblastomas. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_7b20963ea7228d1a6b2c295fbd4705f4 |
| institution | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:2445/111079 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | BioMed Central |
| publisherStr | BioMed Central |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Effect of low doses of actinomycin D on neuroblastoma cell lines Cortés, Constanza Veiga, Sonia Rosa Pereira da Almacellas i Canals, Eugènia Hernández-Losa, Javier Ferreres, Joan C. Kozma, Sara C. Ambrosio Viale, Santiago Thomas, George Tauler Girona, Albert Actinomicetals Apoptosi Cèl·lules Posologia Infants Actinomycetales Apoptosis Cells Posology Children Background: Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. With the intent to find new therapies for neuroblastomas, we investigated the efficacy of low-doses of actinomycin D, which at low concentrations preferentially inhibit RNA polymerase I-dependent rRNA trasncription and therefore, ribosome biogenesis. Methods: Neuroblastoma cell lines with different p53 genetic background were employed to determine the response on cell viability and apoptosis of low-dose of actinomycin D. Subcutaneously-implanted SK-N-JD derived neuroblastoma tumors were used to assess the effect of low-doses of actinomycin D on tumor formation. Results: Low-dose actinomycin D treatment causes a reduction of cell viability in neuroblastoma cell lines and that this effect is stronger in cells that are wild-type for p53. MYCN overexpression contributes to enhance this effect, confirming the importance of this oncogene in ribosome biogenesis. In the wild-type SK-N-JD cell line, apoptosis was the major mechanism responsible for the reduction in viability and we demonstrate that treatment with the MDM2 inhibitor Nutlin-3, had a similar effect to that of actinomycin D. Apoptosis was also detected in p53(-/-)deficient LA1-55n cells treated with actinomycin D, however, only a small recovery of cell viability was found when apoptosis was inhibited by a pan-caspase inhibitor, suggesting that the treatment could activate an apoptosis-independent cell death pathway in these cells. We also determined whether actinomycin D could increase the efficacy of the histone deacetylase inhibitor, SAHA, which is in being used in neuroblastoma clinical trials. We show that actinomycin D synergizes with SAHA in neuroblastoma cell lines. Moreover, on subcutaneously-implanted neuroblastoma tumors derived from SK-N-JD cells, actinomycin D led to tumor regression, an effect enhanced in combination with SAHA. Conclusions: The results presented in this work demonstrate that actinomycin D, at low concentrations, inhibits proliferation and induces cell death in vitro, as well as tumor regression in vivo. From this study, we propose that use of ribosome biogenesis inhibitors should be clinically considered as a potential therapy to treat neuroblastomas. BioMed Central https://hdl.handle.net/2445/111079 |
| spellingShingle | Effect of low doses of actinomycin D on neuroblastoma cell lines Cortés, Constanza Actinomicetals Apoptosi Cèl·lules Posologia Infants Actinomycetales Apoptosis Cells Posology Children |
| status_str | publishedVersion |
| title | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| title_full | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| title_fullStr | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| title_full_unstemmed | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| title_short | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| title_sort | Effect of low doses of actinomycin D on neuroblastoma cell lines |
| topic | Actinomicetals Apoptosi Cèl·lules Posologia Infants Actinomycetales Apoptosis Cells Posology Children |
| topic_facet | Actinomicetals Apoptosi Cèl·lules Posologia Infants Actinomycetales Apoptosis Cells Posology Children |
| url | https://hdl.handle.net/2445/111079 |